47 results on '"Marcin Cieślik"'
Search Results
2. Characterizing the Therapeutic Potential of a Potent BET Degrader in Merkel Cell Carcinoma
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Jae Eun Choi, Monique E. Verhaegen, Sahr Yazdani, Rohit Malik, Paul W. Harms, Doris Mangelberger, Jean Tien, Xuhong Cao, Yuping Wang, Marcin Cieślik, Jonathan Gurkan, Mishaal Yazdani, Xiaojun Jing, Kristin Juckette, Fengyun Su, Rui Wang, Bing Zhou, Ingrid J. Apel, Shaomeng Wang, Andrzej A. Dlugosz, and Arul M. Chinnaiyan
- Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Studies on the efficacy of small molecule inhibitors in Merkel cell carcinoma (MCC) have been limited and largely inconclusive. In this study, we investigated the therapeutic potential of a potent BET degrader, BETd-246, in the treatment of MCC. We found that MCC cell lines were significantly more sensitive to BETd-246 than to BET inhibitor treatment. Therapeutic targeting of BET proteins resulted in a loss of “MCC signature” genes but not MYC expression as previously described irrespective of Merkel cell polyomavirus (MCPyV) status. In MCPyV+ MCC cells, BETd-246 alone suppressed downstream targets in the MCPyV-LT Ag axis. We also found enrichment of HOX and cell cycle genes in MCPyV− MCC cell lines that were intrinsically resistant to BETd-246. Our findings uncover a requirement for BET proteins in maintaining MCC lineage identity and point to the potential utility of BET degraders for treating MCC.
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- 2019
- Full Text
- View/download PDF
3. Identification and Validation of PCAT14 as Prognostic Biomarker in Prostate Cancer
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Sudhanshu Shukla, Xiang Zhang, Yashar S. Niknafs, Lanbo Xiao, Rohit Mehra, Marcin Cieślik, Ashley Ross, Edward Schaeffer, Bhavna Malik, Shuling Guo, Susan M. Freier, Huynh-Hoa Bui, Javed Siddiqui, Xiaojun Jing, Xuhong Cao, Saravana M. Dhanasekaran, Felix Y. Feng, Arul M. Chinnaiyan, and Rohit Malik
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Rapid advances in the discovery of long noncoding RNAs (lncRNAs) have identified lineage- and cancer-specific biomarkers that may be relevant in the clinical management of prostate cancer (PCa). Here we assembled and analyzed a large RNA-seq dataset, from 585 patient samples, including benign prostate tissue and both localized and metastatic PCa to discover and validate differentially expressed genes associated with disease aggressiveness. We performed Sample Set Enrichment Analysis (SSEA) and identified genes associated with low versus high Gleason score in the RNA-seq database. Comparing Gleason 6 versus 9+ PCa samples, we identified 99 differentially expressed genes with variable association to Gleason grade as well as robust expression in prostate cancer. The top-ranked novel lncRNA PCAT14, exhibits both cancer and lineage specificity. On multivariate analysis, low PCAT14 expression independently predicts for BPFS (P = .00126), PSS (P = .0385), and MFS (P = .000609), with trends for OS as well (P = .056). An RNA in-situ hybridization (ISH) assay for PCAT14 distinguished benign vs malignant cases, as well as high vs low Gleason disease. PCAT14 is transcriptionally regulated by AR, and endogenous PCAT14 overexpression suppresses cell invasion. Thus, Using RNA-sequencing data we identify PCAT14, a novel prostate cancer and lineage-specific lncRNA. PCAT14 is highly expressed in low grade disease and loss of PCAT14 predicts for disease aggressiveness and recurrence.
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- 2016
- Full Text
- View/download PDF
4. Supplementary Tables S1-S13 from Cancer Cell Intrinsic and Immunologic Phenotypes Determine Clinical Outcomes in Basal-like Breast Cancer
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Arul M. Chinnaiyan, Dan R. Robinson, Jamie Guenthoer, Peggy Porter, Xuhong Cao, Mei-Tzu C. Tang, Erin Cobain, Lanbo Xiao, Yi-Mi Wu, Marcin Cieślik, Yuping Zhang, and Christopher I. Li
- Abstract
Excel file containing Tables S1 through S13
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- 2023
5. Data from Cancer Cell Intrinsic and Immunologic Phenotypes Determine Clinical Outcomes in Basal-like Breast Cancer
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Arul M. Chinnaiyan, Dan R. Robinson, Jamie Guenthoer, Peggy Porter, Xuhong Cao, Mei-Tzu C. Tang, Erin Cobain, Lanbo Xiao, Yi-Mi Wu, Marcin Cieślik, Yuping Zhang, and Christopher I. Li
- Abstract
Purpose:Basal-like breast cancer (BLBC) is a particularly aggressive intrinsic molecular subtype of breast cancer that lacks targeted therapies. There is also no clinically useful test to risk stratify patients with BLBC. We hypothesized that a transcriptome-based phenotypic characterization of BLBC tumors and their microenvironments may overcome these challenges.Experimental Design:We conducted a retrospective correlative genomic sequencing study using a matched pairs design with validation in five independent cohorts. The study was conducted on a large population-based prospective cohort of the major molecular subtypes of breast cancer conducted in the greater Seattle-Puget Sound metropolitan area. Cases consisted of women 20–69 years of age first diagnosed with invasive breast cancer identified through the population-based Surveillance Epidemiology and End Results program. Patients for this analysis (n = 949) were identified from the 1,408 patients with stage I–III triple-negative breast cancer [estrogen receptor–negative (ER−), progesterone receptor–negative (PR−), HER2−]. Of the 949 women, 248 developed a recurrence after their initial diagnosis. A matched set of 67 recurrent and nonrecurrent BLBC tumors was subjected to transcriptome sequencing. Through RNA sequencing of the matched sets of recurrent and nonrecurrent BLBC tumors, we aimed to identify prognostic phenotypes.To identify nonredundant and uncorrelated prognostic genes, we used an ensemble of variable selection algorithms, which resulted in a ranking of genes on the basis of their expected utility in classification. Using leave-one-out cross-validation, we trained a random forest classifier on the basis of the top 21 genes (BRAVO-DX). Validations were performed in five independent triple-negative or BLBC cohorts, and biomarker robustness and transferability were demonstrated by employing real-time PCR.Results:We found that cancer cell intrinsic and immunologic phenotypes are independent predictors of recurrence. By simultaneously interrogating the tumor and its microenvironment, we developed a compound risk model that stratified patients into low-, medium-, and high-risk groups, with a 14%/56%/74% chance of recurrence, respectively. Biologically, the primary tumors of patients who developed a recurrence had increased growth factor signaling and stem-like features, while nonrecurrent tumors showed high lymphocyte infiltration with clonal expansion of T and B cells, as well as antitumor polarization of macrophages. We validated our model in five independent cohorts, including three large cohorts, where BRAVO-DX was highly informative in identifying patients with disease recurrence [HR, 6.79 (95% confidence interval (CI), 1.89–24.37); HR, 3.45 (95% CI, 2.41–4.93); and HR, 1.69 (95% CI, 1.17–2.46)]. A smaller gene set focused on the tumor immunophenotype, BRAVO-IMMUNE, was highly prognostic in all five cohorts.Conclusions:Together, these results indicate that phenotypic characteristics of BLBCs and their microenvironment are associated with recurrence-free survival and demonstrate the utility of intrinsic and extrinsic phenotypes as independent prognostic biomarkers in BLBC. Pending further evaluation and validation, our prognostic model has the potential to inform clinical decision-making for patients with BLBC as it identifies those at high risk of rapidly progressing on standard chemotherapy, as well as those who may benefit from alternative first-line therapies.
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- 2023
6. Supplementary Figures S1-S10 from Cancer Cell Intrinsic and Immunologic Phenotypes Determine Clinical Outcomes in Basal-like Breast Cancer
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Arul M. Chinnaiyan, Dan R. Robinson, Jamie Guenthoer, Peggy Porter, Xuhong Cao, Mei-Tzu C. Tang, Erin Cobain, Lanbo Xiao, Yi-Mi Wu, Marcin Cieślik, Yuping Zhang, and Christopher I. Li
- Abstract
Supplementary Figures S1 through S10
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- 2023
7. Cancer Cell Intrinsic and Immunologic Phenotypes Determine Clinical Outcomes in Basal-like Breast Cancer
- Author
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Lanbo Xiao, Yuping Zhang, Arul M. Chinnaiyan, Christopher I. Li, Dan R. Robinson, Marcin Cieślik, Yi-Mi Wu, Jamie Guenthoer, Xuhong Cao, Peggy L. Porter, Mei-Tzu C. Tang, and Erin F. Cobain
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,education.field_of_study ,business.industry ,Population ,Disease ,medicine.disease ,Transcriptome ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Breast cancer ,030220 oncology & carcinogenesis ,Internal medicine ,Surveillance, Epidemiology, and End Results ,Medicine ,Biomarker (medicine) ,Stage (cooking) ,business ,Prospective cohort study ,education - Abstract
Purpose: Basal-like breast cancer (BLBC) is a particularly aggressive intrinsic molecular subtype of breast cancer that lacks targeted therapies. There is also no clinically useful test to risk stratify patients with BLBC. We hypothesized that a transcriptome-based phenotypic characterization of BLBC tumors and their microenvironments may overcome these challenges. Experimental Design: We conducted a retrospective correlative genomic sequencing study using a matched pairs design with validation in five independent cohorts. The study was conducted on a large population-based prospective cohort of the major molecular subtypes of breast cancer conducted in the greater Seattle-Puget Sound metropolitan area. Cases consisted of women 20–69 years of age first diagnosed with invasive breast cancer identified through the population-based Surveillance Epidemiology and End Results program. Patients for this analysis (n = 949) were identified from the 1,408 patients with stage I–III triple-negative breast cancer [estrogen receptor–negative (ER−), progesterone receptor–negative (PR−), HER2−]. Of the 949 women, 248 developed a recurrence after their initial diagnosis. A matched set of 67 recurrent and nonrecurrent BLBC tumors was subjected to transcriptome sequencing. Through RNA sequencing of the matched sets of recurrent and nonrecurrent BLBC tumors, we aimed to identify prognostic phenotypes. To identify nonredundant and uncorrelated prognostic genes, we used an ensemble of variable selection algorithms, which resulted in a ranking of genes on the basis of their expected utility in classification. Using leave-one-out cross-validation, we trained a random forest classifier on the basis of the top 21 genes (BRAVO-DX). Validations were performed in five independent triple-negative or BLBC cohorts, and biomarker robustness and transferability were demonstrated by employing real-time PCR. Results: We found that cancer cell intrinsic and immunologic phenotypes are independent predictors of recurrence. By simultaneously interrogating the tumor and its microenvironment, we developed a compound risk model that stratified patients into low-, medium-, and high-risk groups, with a 14%/56%/74% chance of recurrence, respectively. Biologically, the primary tumors of patients who developed a recurrence had increased growth factor signaling and stem-like features, while nonrecurrent tumors showed high lymphocyte infiltration with clonal expansion of T and B cells, as well as antitumor polarization of macrophages. We validated our model in five independent cohorts, including three large cohorts, where BRAVO-DX was highly informative in identifying patients with disease recurrence [HR, 6.79 (95% confidence interval (CI), 1.89–24.37); HR, 3.45 (95% CI, 2.41–4.93); and HR, 1.69 (95% CI, 1.17–2.46)]. A smaller gene set focused on the tumor immunophenotype, BRAVO-IMMUNE, was highly prognostic in all five cohorts. Conclusions: Together, these results indicate that phenotypic characteristics of BLBCs and their microenvironment are associated with recurrence-free survival and demonstrate the utility of intrinsic and extrinsic phenotypes as independent prognostic biomarkers in BLBC. Pending further evaluation and validation, our prognostic model has the potential to inform clinical decision-making for patients with BLBC as it identifies those at high risk of rapidly progressing on standard chemotherapy, as well as those who may benefit from alternative first-line therapies.
- Published
- 2021
8. A novel ATXN1-DUX4 fusion expands the spectrum of ‘CIC-rearranged sarcoma’ of the CNS to include non-CIC alterations
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Rohit Mehra, Martha Quezado, Rajen Mody, Kenneth Aldape, Marcin Cieślik, Drew Pratt, Andrea Franson, Arul M. Chinnaiyan, Evan Cantor, Hong Xiao, Zied Abdullaev, Chandan Kumar-Sinha, Lina Shao, and Sandra Camelo-Piragua
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Homeodomain Proteins ,Male ,CIC-Rearranged Sarcoma ,Oncogene Proteins, Fusion ,Brain Neoplasms ,business.industry ,Sarcoma ,Biology ,Pathology and Forensic Medicine ,Cellular and Molecular Neuroscience ,Text mining ,DUX4 ,Child, Preschool ,Cancer research ,Humans ,Neurology (clinical) ,business ,Ataxin-1 - Published
- 2021
9. PIKfyve, expressed by CD11c-positive cells, controls tumor immunity
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Jae Eun Choi, Yuanyuan Qiao, Ilona Kryczek, Jiali Yu, Jonathan Gurkan, Yi Bao, Mahnoor Gondal, Jean Ching-Yi Tien, Tomasz Maj, Sahr Yazdani, Abhijit Parolia, Houjun Xia, JiaJia Zhou, Shuang Wei, Sara Grove, Linda Vatan, Heng Lin, Gaopeng Li, Yang Zheng, Yuping Zhang, Xuhong Cao, Fengyun Su, Rui Wang, Tongchen He, Marcin Cieslik, Michael D. Green, Weiping Zou, and Arul M. Chinnaiyan
- Subjects
Science - Abstract
Abstract Cancer treatment continues to shift from utilizing traditional therapies to targeted ones, such as protein kinase inhibitors and immunotherapy. Mobilizing dendritic cells (DC) and other myeloid cells with antigen presenting and cancer cell killing capacities is an attractive but not fully exploited approach. Here, we show that PIKFYVE is a shared gene target of clinically relevant protein kinase inhibitors and high expression of this gene in DCs is associated with poor patient response to immune checkpoint blockade (ICB) therapy. Genetic and pharmacological studies demonstrate that PIKfyve ablation enhances the function of CD11c+ cells (predominantly dendritic cells) via selectively altering the non-canonical NF-κB pathway. Both loss of Pikfyve in CD11c+ cells and treatment with apilimod, a potent and specific PIKfyve inhibitor, restrained tumor growth, enhanced DC-dependent T cell immunity, and potentiated ICB efficacy in tumor-bearing mouse models. Furthermore, the combination of a vaccine adjuvant and apilimod reduced tumor progression in vivo. Thus, PIKfyve negatively regulates the function of CD11c+ cells, and PIKfyve inhibition has promise for cancer immunotherapy and vaccine treatment strategies.
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- 2024
- Full Text
- View/download PDF
10. Integrative multi-region molecular profiling of primary prostate cancer in men with synchronous lymph node metastasis
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Udit Singhal, Srinivas Nallandhighal, Jeffrey J. Tosoian, Kevin Hu, Trinh M. Pham, Judith Stangl-Kremser, Chia-Jen Liu, Razeen Karim, Komal R. Plouffe, Todd M. Morgan, Marcin Cieslik, Roberta Lucianò, Shahrokh F. Shariat, Nadia Finocchio, Lucia Dambrosio, Claudio Doglioni, Arul M. Chinnaiyan, Scott A. Tomlins, Alberto Briganti, Ganesh S. Palapattu, Aaron M. Udager, and Simpa S. Salami
- Subjects
Science - Abstract
Abstract Localized prostate cancer is frequently composed of multiple spatially distinct tumors with significant inter- and intra-tumoral molecular heterogeneity. This genomic diversity gives rise to many competing clones that may drive the biological trajectory of the disease. Previous large-scale sequencing efforts have focused on the evolutionary process in metastatic prostate cancer, revealing a potential clonal progression to castration resistance. However, the clonal origin of synchronous lymph node (LN) metastases in primary disease is still unknown. Here, we perform multi-region, targeted next generation sequencing and construct phylogenetic trees in men with prostate cancer with synchronous LN metastasis to better define the pathologic and molecular features of primary disease most likely to spread to the LNs. Collectively, we demonstrate that a combination of histopathologic and molecular factors, including tumor grade, presence of extra-prostatic extension, cellular morphology, and oncogenic genomic alterations are associated with synchronous LN metastasis.
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- 2024
- Full Text
- View/download PDF
11. A systematic overview of single-cell transcriptomics databases, their use cases, and limitations
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Mahnoor N. Gondal, Saad Ur Rehman Shah, Arul M. Chinnaiyan, and Marcin Cieslik
- Subjects
single-cell RNA-seq ,single-cell databases ,single-cell atlases ,single-cell data analysis ,web-based platforms ,cell heterogeneity ,Computer applications to medicine. Medical informatics ,R858-859.7 - Abstract
Rapid advancements in high-throughput single-cell RNA-seq (scRNA-seq) technologies and experimental protocols have led to the generation of vast amounts of transcriptomic data that populates several online databases and repositories. Here, we systematically examined large-scale scRNA-seq databases, categorizing them based on their scope and purpose such as general, tissue-specific databases, disease-specific databases, cancer-focused databases, and cell type-focused databases. Next, we discuss the technical and methodological challenges associated with curating large-scale scRNA-seq databases, along with current computational solutions. We argue that understanding scRNA-seq databases, including their limitations and assumptions, is crucial for effectively utilizing this data to make robust discoveries and identify novel biological insights. Such platforms can help bridge the gap between computational and wet lab scientists through user-friendly web-based interfaces needed for democratizing access to single-cell data. These platforms would facilitate interdisciplinary research, enabling researchers from various disciplines to collaborate effectively. This review underscores the importance of leveraging computational approaches to unravel the complexities of single-cell data and offers a promising direction for future research in the field.
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- 2024
- Full Text
- View/download PDF
12. Proteogenomic and metabolomic characterization of human glioblastoma
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Cristina E. Tognon, Larisa Polonskaya, Tara Skelly, Shuang Cai, Francesmary Modugno, Larissa Rossell, Nancy Roche, Chen Huang, Jessika Baral, Fulvio D'Angelo, Wen-Wei Liang, Chia-Feng Tsai, Sneha P. Couvillion, Karin D. Rodland, Jun Zhu, Liang-Bo Wang, Paul D. Piehowski, Antonio Colaprico, Anupriya Agarwal, Matthew A. Wyczalkowski, Umut Ozbek, Francesca Petralia, Alexis Demopoulos, William W. Maggio, Lin Chen, Katherine A. Hoadley, Richard D. Smith, Sandra Cottingham, John McGee, Marcin J. Domagalski, Houxiang Zhu, Emek Demir, Rebecca I. Montgomery, Jamie Moon, Rashna Madan, George D. Wilson, Luciano Garofano, Ewa P. Malc, Chelsea J. Newton, Steven A. Carr, Chandan Kumar-Sinha, Donghui Tan, Christopher R. Kinsinger, Oxana Paklina, Weiqing Wan, Stephanie De Young, Sandra Cerda, Shankha Satpathy, Wojciech Kaspera, Linda Hannick, Gad Getz, Runyu Hong, Shuangjia Lu, Ziad Hanhan, Daniel C. Rohrer, Annette Marrero-Oliveras, Wojciech Szopa, Yuxing Liao, Amanda G. Paulovich, Jiayi Ji, Denis A. Golbin, Tara Hiltke, Weiva Sieh, Piotr A. Mieczkowski, Matthew E. Monroe, Gilbert S. Omenn, Jill S. Barnholtz-Sloan, Azra Krek, Bing Zhang, Brittany Henderson, Peter B. McGarvey, Ratna R. Thangudu, Maciej Wiznerowicz, Saravana M. Dhanasekaran, Alex Webster, Kai Li, Karna Robinson, Nan Ji, Karl K. Weitz, Simina M. Boca, Xiaoyu Song, Anna Calinawan, Adam C. Resnick, Brian J. Druker, Dana R. Valley, David J. Clark, Tao Liu, Eric J. Jaehnig, Alicia Francis, Michele Ceccarelli, Rui Zhao, Dmitry Rykunov, Boris Reva, Elizabeth R. Duffy, Antonio Iavarone, Dave Tabor, Joshua F. McMichael, Daniel Cui Zhou, Maureen Dyer, Kimberly Elburn, Scott D. Jewell, Negin Vatanian, Shirley Tsang, Seungyeul Yoo, Alexander R. Pico, Grace Zhao, Kent J. Bloodsworth, Chet Birger, Jena Lilly, Eunkyung An, Jeffrey R. Whiteaker, Albert H. Kim, Yige Wu, Karen A. Ketchum, Felipe D. Leprevost, Alcida Karz, Uma Borate, Nathan Edwards, Uma Velvulou, Melissa Borucki, Vasileios Stathias, Sanford P. Markey, Corbin D. Jones, Ronald J. Moore, MacIntosh Cornwell, Karsten Krug, Michael J. Birrer, James Suh, Tomasz Czernicki, Jason E. McDermott, Emily S. Boja, Pei Wang, Nina Martinez, Wenke Liu, Yan Shi, Lili Blumenberg, Emily Kawaler, Jeffrey W. Tyner, Feng Chen, Jakub Stawicki, Ki Sung Um, Arul M. Chinnaiyan, Robert Zelt, Jacob J. Day, Zhen Zhang, Caleb M. Lindgren, Li Ding, Nikolay Gabrovski, Hongwei Liu, Jonathan T. Lei, Alla Karpova, Ramani B. Kothadia, Sailaja Mareedu, Mitual Amin, Hannah Boekweg, Jennifer E. Kyle, Sara R. Savage, Brian R. Rood, Yuriy Zakhartsev, Matthew L. Anderson, Alyssa Charamut, Wagma Caravan, Shakti Ramkissoon, Junmei Wang, Song Cao, Samuel H. Payne, Rosalie K. Chu, Rajiv Dhir, David W. Andrews, Galen Hostetter, Liqun Qi, Zhiao Shi, Milan G. Chheda, Robert Edwards, Hui Zhang, Weiping Ma, Jennifer M. Eschbacher, Stacey Gabriel, Jan Lubinski, Lijun Yao, Erika M. Zink, Kelly L. Stratton, William Bocik, Mathangi Thiagarajan, Shilpi Singh, Michael A. Gillette, Lisa M. Bramer, Thomas L. Bauer, Michael Vernon, Henry Rodriguez, Dimitris G. Placantonakis, Eric E. Schadt, Alexey I. Nesvizhskii, Vladislav A. Petyuk, Ana I. Robles, Yvonne Shutack, Anna Malovannaya, Stephen E. Stein, Xi Chen, Lyndon Kim, Yize Li, Shannon Richey, Stephan C. Schürer, Barbara Hindenach, Matthew J. Ellis, Yongchao Dou, David Fenyö, Amy M. Perou, Olga Potapova, Shrabanti Chowdhury, Andrew K. Godwin, Marcin Cieślik, Michael C. Wendl, Marina A. Gritsenko, Pietro Pugliese, Elie Traer, Simona Migliozzi, D. R. Mani, Houston Culpepper, Gregory J. Riggins, Xiaolu Yang, Mehdi Mesri, David Chesla, Lindsey K. Olsen, Lori J. Sokoll, Suhas Vasaikar, Liwei Zhang, Meghan C. Burke, Kelly V. Ruggles, Qing Kay Li, Daniel W. Chan, Bo Wen, Nicollette Maunganidze, Darlene Tansil, Joseph H. Rothstein, Barbara Pruetz, Pushpa Hariharan, Wang, L. -B., Karpova, A., Gritsenko, M. A., Kyle, J. E., Cao, S., Li, Y., Rykunov, D., Colaprico, A., Rothstein, J. H., Hong, R., Stathias, V., Cornwell, M., Petralia, F., Wu, Y., Reva, B., Krug, K., Pugliese, P., Kawaler, E., Olsen, L. K., Liang, W. -W., Song, X., Dou, Y., Wendl, M. C., Caravan, W., Liu, W., Cui Zhou, D., Ji, J., Tsai, C. -F., Petyuk, V. A., Moon, J., Ma, W., Chu, R. K., Weitz, K. K., Moore, R. J., Monroe, M. E., Zhao, R., Yang, X., Yoo, S., Krek, A., Demopoulos, A., Zhu, H., Wyczalkowski, M. A., Mcmichael, J. F., Henderson, B. L., Lindgren, C. M., Boekweg, H., Lu, S., Baral, J., Yao, L., Stratton, K. G., Bramer, L. M., Zink, E., Couvillion, S. P., Bloodsworth, K. J., Satpathy, S., Sieh, W., Boca, S. M., Schurer, S., Chen, F., Wiznerowicz, M., Ketchum, K. A., Boja, E. S., Kinsinger, C. R., Robles, A. I., Hiltke, T., Thiagarajan, M., Nesvizhskii, A. I., Zhang, B., Mani, D. R., Ceccarelli, M., Chen, X. S., Cottingham, S. L., Li, Q. K., Kim, A. H., Fenyo, D., Ruggles, K. V., Rodriguez, H., Mesri, M., Payne, S. H., Resnick, A. C., Wang, P., Smith, R. D., Iavarone, A., Chheda, M. G., Barnholtz-Sloan, J. S., Rodland, K. D., Liu, T., Ding, L., Agarwal, A., Amin, M., An, E., Anderson, M. L., Andrews, D. W., Bauer, T., Birger, C., Birrer, M. J., Blumenberg, L., Bocik, W. E., Borate, U., Borucki, M., Burke, M. C., Cai, S., Calinawan, A. P., Carr, S. A., Cerda, S., Chan, D. W., Charamut, A., Chen, L. S., Chesla, D., Chinnaiyan, A. M., Chowdhury, S., Cieslik, M. P., Clark, D. J., Culpepper, H., Czernicki, T., D'Angelo, F., Day, J., De Young, S., Demir, E., Dhanasekaran, S. M., Dhir, R., Domagalski, M. J., Druker, B., Duffy, E., Dyer, M., Edwards, N. J., Edwards, R., Elburn, K., Ellis, M. J., Eschbacher, J., Francis, A., Gabriel, S., Gabrovski, N., Garofano, L., Getz, G., Gillette, M. A., Godwin, A. K., Golbin, D., Hanhan, Z., Hannick, L. I., Hariharan, P., Hindenach, B., Hoadley, K. A., Hostetter, G., Huang, C., Jaehnig, E., Jewell, S. D., Ji, N., Jones, C. D., Karz, A., Kaspera, W., Kim, L., Kothadia, R. B., Kumar-Sinha, C., Lei, J., Leprevost, F. D., Li, K., Liao, Y., Lilly, J., Liu, H., Lubinski, J., Madan, R., Maggio, W., Malc, E., Malovannaya, A., Mareedu, S., Markey, S. P., Marrero-Oliveras, A., Martinez, N., Maunganidze, N., Mcdermott, J. E., Mcgarvey, P. B., Mcgee, J., Mieczkowski, P., Migliozzi, S., Modugno, F., Montgomery, R., Newton, C. J., Omenn, G. S., Ozbek, U., Paklina, O. V., Paulovich, A. G., Perou, A. M., Pico, A. R., Piehowski, P. D., Placantonakis, D. G., Polonskaya, L., Potapova, O., Pruetz, B., Qi, L., Ramkissoon, S., Resnick, A., Richey, S., Riggins, G., Robinson, K., Roche, N., Rohrer, D. C., Rood, B. R., Rossell, L., Savage, S. R., Schadt, E. E., Shi, Y., Shi, Z., Shutack, Y., Singh, S., Skelly, T., Sokoll, L. J., Stawicki, J., Stein, S. E., Suh, J., Szopa, W., Tabor, D., Tan, D., Tansil, D., Thangudu, R. R., Tognon, C., Traer, E., Tsang, S., Tyner, J., Um, K. S., Valley, D. R., Vasaikar, S., Vatanian, N., Velvulou, U., Vernon, M., Wan, W., Wang, J., Webster, A., Wen, B., Whiteaker, J. R., Wilson, G. D., Zakhartsev, Y., Zelt, R., Zhang, H., Zhang, L., Zhang, Z., Zhao, G., and Zhu, J.
- Subjects
Proteomics ,0301 basic medicine ,Cancer Research ,CPTAC ,Histone H2B acetylation ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,Computational biology ,Biology ,Article ,03 medical and health sciences ,lipidome ,0302 clinical medicine ,Metabolomics ,proteogenomic ,Humans ,Phosphorylation ,EP300 ,proteomic ,Proteogenomics ,acetylome ,single nuclei RNA-seq ,Brain Neoplasms ,Phospholipase C gamma ,glioblastoma ,Computational Biology ,Lipidome ,030104 developmental biology ,Histone ,Oncology ,Acetylation ,030220 oncology & carcinogenesis ,Mutation ,biology.protein ,metabolome ,signaling - Abstract
Glioblastoma (GBM) is the most aggressive nervous system cancer. Understanding its molecular pathogenesis is crucial to improving diagnosis and treatment. Integrated analysis of genomic, proteomic, post-translational modification and metabolomic data on 99 treatment-naive GBMs provides insights to GBM biology. We identify key phosphorylation events (e.g., phosphorylated PTPN11 and PLCG1) as potential switches mediating oncogenic pathway activation, as well as potential targets for EGFR-, TP53-, and RB1-altered tumors. Immune subtypes with distinct immune cell types are discovered using bulk omics methodologies, validated by snRNA-seq, and correlated with specific expression and histone acetylation patterns. Histone H2B acetylation in classical-like and immune-low GBM is driven largely by BRDs, CREBBP, and EP300. Integrated metabolomic and proteomic data identify specific lipid distributions across subtypes and distinct global metabolic changes in IDH-mutated tumors. This work highlights biological relationships that could contribute to stratification of GBM patients for more effective treatment. Wang et al. perform integrated proteogenomic analysis of adult glioblastoma (GBM), including metabolomics, lipidomics, and single nuclei RNA-Seq, revealing insights into the immune landscape of GBM, cell-specific nature of EMT signatures, histone acetylation in classical GBM, and the existence of signaling hubs which could provide therapeutic vulnerabilities.
- Published
- 2021
13. Cancer Cell Intrinsic and Immunologic Phenotypes Determine Clinical Outcomes in Basal-like Breast Cancer
- Author
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Christopher I, Li, Yuping, Zhang, Marcin, Cieślik, Yi-Mi, Wu, Lanbo, Xiao, Erin, Cobain, Mei-Tzu C, Tang, Xuhong, Cao, Peggy, Porter, Jamie, Guenthoer, Dan R, Robinson, and Arul M, Chinnaiyan
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Adult ,Washington ,Whole Genome Sequencing ,Breast Neoplasms ,Middle Aged ,Pregnanes ,Prognosis ,Phenotype ,Tumor Microenvironment ,Humans ,Female ,Glycosides ,Prospective Studies ,Neoplasm Recurrence, Local ,Transcriptome ,Aged - Abstract
Basal-like breast cancer (BLBC) is a particularly aggressive intrinsic molecular subtype of breast cancer that lacks targeted therapies. There is also no clinically useful test to risk stratify patients with BLBC. We hypothesized that a transcriptome-based phenotypic characterization of BLBC tumors and their microenvironments may overcome these challenges.We conducted a retrospective correlative genomic sequencing study using a matched pairs design with validation in five independent cohorts. The study was conducted on a large population-based prospective cohort of the major molecular subtypes of breast cancer conducted in the greater Seattle-Puget Sound metropolitan area. Cases consisted of women 20-69 years of age first diagnosed with invasive breast cancer identified through the population-based Surveillance Epidemiology and End Results program. Patients for this analysis (We found that cancer cell intrinsic and immunologic phenotypes are independent predictors of recurrence. By simultaneously interrogating the tumor and its microenvironment, we developed a compound risk model that stratified patients into low-, medium-, and high-risk groups, with a 14%/56%/74% chance of recurrence, respectively. Biologically, the primary tumors of patients who developed a recurrence had increased growth factor signaling and stem-like features, while nonrecurrent tumors showed high lymphocyte infiltration with clonal expansion of T and B cells, as well as antitumor polarization of macrophages. We validated our model in five independent cohorts, including three large cohorts, where BRAVO-DX was highly informative in identifying patients with disease recurrence [HR, 6.79 (95% confidence interval (CI), 1.89-24.37); HR, 3.45 (95% CI, 2.41-4.93); and HR, 1.69 (95% CI, 1.17-2.46)]. A smaller gene set focused on the tumor immunophenotype, BRAVO-IMMUNE, was highly prognostic in all five cohorts.Together, these results indicate that phenotypic characteristics of BLBCs and their microenvironment are associated with recurrence-free survival and demonstrate the utility of intrinsic and extrinsic phenotypes as independent prognostic biomarkers in BLBC. Pending further evaluation and validation, our prognostic model has the potential to inform clinical decision-making for patients with BLBC as it identifies those at high risk of rapidly progressing on standard chemotherapy, as well as those who may benefit from alternative first-line therapies.
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- 2020
14. Epigenetic driver mutations in ARID1A shape cancer immune phenotype and immunotherapy
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Michael D. Green, Arul M. Chinnaiyan, Weiping Zou, Lili Zhao, Weimin Wang, Kathleen R. Cho, Mengyao Tan, Jipeng Guo, Heng Lin, Weichao Wang, Jiajia Zhou, David G. Huntsman, Yali Dou, Shuang Wei, Yajia Zhang, Xiaojun Jing, Marcin Cieślik, Timothy A. Chan, Linda Vatan, Gaopeng Li, Rugang Zhang, Jing Li, Wei Li, Ilona Kryczek, and Benjamin G. Bitler
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0301 basic medicine ,medicine.medical_treatment ,T cell ,Biology ,Chromatin remodeling ,Epigenesis, Genetic ,Immunophenotyping ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,Lymphocytes, Tumor-Infiltrating ,Cancer immunotherapy ,Cell Line, Tumor ,Neoplasms ,medicine ,Animals ,Humans ,Enhancer of Zeste Homolog 2 Protein ,Epigenetics ,Melanoma ,Ovarian Neoplasms ,EZH2 ,General Medicine ,Immunotherapy ,Chromatin Assembly and Disassembly ,Chromatin ,DNA-Binding Proteins ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,Female ,Tumor Escape ,Interferons ,Signal Transduction ,Transcription Factors ,Research Article - Abstract
Whether mutations in cancer driver genes directly affect cancer immune phenotype and T cell immunity remains a standing question. ARID1A is a core member of the polymorphic BRG/BRM-associated factor chromatin remodeling complex. ARID1A mutations occur in human cancers and drive cancer development. Here, we studied the molecular, cellular, and clinical impact of ARID1A aberrations on cancer immunity. We demonstrated that ARID1A aberrations resulted in limited chromatin accessibility to IFN-responsive genes, impaired IFN gene expression, anemic T cell tumor infiltration, poor tumor immunity, and shortened host survival in many human cancer histologies and in murine cancer models. Impaired IFN signaling was associated with poor immunotherapy response. Mechanistically, ARID1A interacted with EZH2 via its carboxyl terminal and antagonized EZH2-mediated IFN responsiveness. Thus, the interaction between ARID1A and EZH2 defines cancer IFN responsiveness and immune evasion. Our work indicates that cancer epigenetic driver mutations can shape cancer immune phenotype and immunotherapy.
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- 2019
15. Next-generation RNA Sequencing-based Biomarker Characterization of Chromophobe Renal Cell Carcinoma and Related Oncocytic Neoplasms
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Lisha Wang, Pankaj Vats, Saravana M. Dhanasekaran, Fengyun Su, Jin Chen, Pedram Argani, Thomas J. Giordano, Rahul Mannan, Arul M. Chinnaiyan, Xiaoming Wang, Sathiya Pandi Narayanan, Rohit Mehra, Stephanie L. Skala, Xuhong Cao, Marcin Cieślik, Yuping Zhang, and Javed Siddiqui
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Pathology ,medicine.medical_specialty ,Urology ,Chromophobe Renal Cell Carcinoma ,030232 urology & nephrology ,Chromophobe cell ,Gene mutation ,urologic and male genital diseases ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Renal cell carcinoma ,medicine ,Humans ,Oncocytoma ,Carcinoma, Renal Cell ,biology ,business.industry ,Sequence Analysis, RNA ,High-Throughput Nucleotide Sequencing ,medicine.disease ,Kidney Neoplasms ,RHCG ,030220 oncology & carcinogenesis ,biology.protein ,Biomarker (medicine) ,Immunohistochemistry ,business - Abstract
Background Renal cell carcinomas (RCCs) are a heterogeneous group of neoplasms. Recent sequencing studies revealed various molecular features associated with histologic RCC subtypes, including chromophobe renal cell carcinoma (ChRCC). Objective To characterize the gene expression and biomarker signatures associated with ChRCC. Design, setting, and participants We performed integrative analysis on RNA sequencing data available from 1049 RCC specimens from The Cancer Genome Atlas and in-house studies. Our workflow identified genes relatively enriched in ChRCC, including Forkhead box I1 (FOXI1), Rh family C glycoprotein (RHCG), and LINC01187. We assessed the expression pattern of FOXI1 and RHCG protein by immunohistochemistry (IHC) and LINC01187 mRNA by RNA in situ hybridization (RNA-ISH) in whole tissue sections representing a cohort of 197 RCC cases, including both primary and metastatic tumors. Outcome measurements and statistical analysis The FOXI1 and RHCG IHC staining, as well as the LINC01187 RNA-ISH staining, was evaluated in each case for intensity, pattern, and localization of expression. Results and limitations All primary and metastatic classic ChRCCs demonstrated homogeneous positive labeling for FOXI1, RHCG proteins, and LINC01187 transcript. Unclassified RCC with oncocytic features, oncocytoma, and hybrid oncocytic tumor, as well as all but two cases of eosinophilic ChRCC also stained positive. Importantly, metastatic and primary RCC of all other subtypes did not demonstrate any unequivocal staining for FOXI1, RHCG, or LINC01187. In normal kidney, FOXI1, RHCG, and LINC01187 were detected in the distal nephron segment, specifically in intercalated cells. Two cases of eosinophilic ChRCC with focal expression of FOXI1 and LINC01187, and Golgi-like RHCG staining were found to contain MTOR gene mutations upon DNA sequencing. Conclusions We demonstrate a pipeline for the identification and validation of RCC subtype–specific biomarkers that can aid in the confirmation of cell of origin and may facilitate accurate classification and diagnosis of renal tumors. Patient summary FOXI1, RHCG, and LINC01187 are lineage-specific signature genes for chromophobe renal cell carcinoma.
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- 2019
16. Analysis of the androgen receptor–regulated lncRNA landscape identifies a role for ARLNC1 in prostate cancer progression
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Susan M. Freier, Mats Ljungman, Lanbo Xiao, Sahr Yazdani, Kristin M. Juckette, Andrew T. Watt, Mona Batish, Shuling Guo, Alexander R. Gawronski, Saravana M. Dhanasekaran, Sudhanshu Shukla, John T. Wei, Michael Uhl, Rohit Malik, Hui Jiang, Yasuyuki Hosono, Yashar S. Niknafs, Yuanyuan Qiao, Utsav Patel, Sethuramasundaram Pitchiaya, Rohit Mehra, Lakshmi P. Kunju, Michelle T. Paulsen, Felix Y. Feng, Rolf Backofen, Xia Jiang, Xuhong Cao, Shruthi Subramaniam, Cenk Sahinalp, Tzu-Ying Liu, Jean C.-Y. Tien, Matthew K. Iyer, Girish C. Shukla, Arul M. Chinnaiyan, Yajia Zhang, Marcin Cieślik, and Lisha Wang
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Male ,0301 basic medicine ,Biology ,Medical and Health Sciences ,Article ,Cell Line ,Androgen ,Transcriptome ,03 medical and health sciences ,Prostate cancer ,Prostate ,androgen receptor ,Cell Line, Tumor ,Receptors ,Genetics ,medicine ,Humans ,Regulation of gene expression ,Neoplastic ,Gene knockdown ,Tumor ,long non-coding RNA ,ARLNC1 ,Prostatic Neoplasms ,Biological Sciences ,prostate cancer ,medicine.disease ,Long non-coding RNA ,3. Good health ,Gene Expression Regulation, Neoplastic ,Androgen receptor ,030104 developmental biology ,medicine.anatomical_structure ,Gene Expression Regulation ,Receptors, Androgen ,Disease Progression ,Androgens ,Cancer research ,RNA ,RNA, Long Noncoding ,Long Noncoding ,Signal transduction ,Signal Transduction ,Developmental Biology - Abstract
The androgen receptor (AR) plays a critical role in the development of the normal prostate as well as prostate cancer. Using an integrative transcriptomic analysis of prostate cancer cell lines and tissues, we identified ARLNC1 (AR-regulated long noncoding RNA 1) as an important long noncoding RNA that is strongly associated with AR signaling in prostate cancer progression. Not only was ARLNC1 induced by the AR protein, but ARLNC1 stabilized the AR transcript via RNA-RNA interaction. ARLNC1 knockdown suppressed AR expression, global AR signaling and prostate cancer growth in vitro and in vivo. Taken together, these data support a role for ARLNC1 in maintaining a positive feedback loop that potentiates AR signaling during prostate cancer progression and identify ARLNC1 as a novel therapeutic target.
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- 2018
17. Cancer transcriptome profiling at the juncture of clinical translation
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Marcin Cieślik and Arul M. Chinnaiyan
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0301 basic medicine ,Sequence Analysis, RNA ,Sequence analysis ,Gene Expression Profiling ,High-Throughput Nucleotide Sequencing ,Cancer ,Context (language use) ,Translation (biology) ,Computational biology ,Biology ,medicine.disease ,Phenotype ,Neoplasm genetics ,Transcriptome ,03 medical and health sciences ,030104 developmental biology ,Neoplasms ,Genetics ,medicine ,Animals ,Humans ,Transcriptome profiling ,RNA, Neoplasm ,Molecular Biology ,Genetics (clinical) - Abstract
Methodological breakthroughs over the past four decades have repeatedly revolutionized transcriptome profiling. Using RNA sequencing (RNA-seq), it has now become possible to sequence and quantify the transcriptional outputs of individual cells or thousands of samples. These transcriptomes provide a link between cellular phenotypes and their molecular underpinnings, such as mutations. In the context of cancer, this link represents an opportunity to dissect the complexity and heterogeneity of tumours and to discover new biomarkers or therapeutic strategies. Here, we review the rationale, methodology and translational impact of transcriptome profiling in cancer.
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- 2017
18. Loss of LCMT1 and biased protein phosphatase 2A heterotrimerization drive prostate cancer progression and therapy resistance
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Reyaz ur Rasool, Caitlin M. O’Connor, Chandan Kanta Das, Mohammed Alhusayan, Brijesh Kumar Verma, Sehbanul Islam, Ingrid E. Frohner, Qu Deng, Erick Mitchell-Velasquez, Jaya Sangodkar, Aqila Ahmed, Sarah Linauer, Ingrid Mudrak, Jessica Rainey, Kaitlin P. Zawacki, Tahra K. Suhan, Catherine G. Callahan, Ryan Rebernick, Ramakrishnan Natesan, Javed Siddiqui, Guido Sauter, Dafydd Thomas, Shaomeng Wang, Derek J. Taylor, Ronald Simon, Marcin Cieslik, Arul M. Chinnaiyan, Luca Busino, Egon Ogris, Goutham Narla, and Irfan A. Asangani
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Science - Abstract
Abstract Loss of the tumor suppressive activity of the protein phosphatase 2A (PP2A) is associated with cancer, but the underlying molecular mechanisms are unclear. PP2A holoenzyme comprises a heterodimeric core, a scaffolding A subunit and a catalytic C subunit, and one of over 20 distinct substrate-directing regulatory B subunits. Methylation of the C subunit regulates PP2A heterotrimerization, affecting B subunit binding and substrate specificity. Here, we report that the leucine carboxy methyltransferase (LCMT1), which methylates the L309 residue of the C subunit, acts as a suppressor of androgen receptor (AR) addicted prostate cancer (PCa). Decreased methyl-PP2A-C levels in prostate tumors is associated with biochemical recurrence and metastasis. Silencing LCMT1 increases AR activity and promotes castration-resistant prostate cancer growth. LCMT1-dependent methyl-sensitive AB56αCme heterotrimers target AR and its critical coactivator MED1 for dephosphorylation, resulting in the eviction of the AR-MED1 complex from chromatin and loss of target gene expression. Mechanistically, LCMT1 is regulated by S6K1-mediated phosphorylation-induced degradation requiring the β-TRCP, leading to acquired resistance to anti-androgens. Finally, feedforward stabilization of LCMT1 by small molecule activator of phosphatase (SMAP) results in attenuation of AR-signaling and tumor growth inhibition in anti-androgen refractory PCa. These findings highlight methyl-PP2A-C as a prognostic marker and that the loss of LCMT1 is a major determinant in AR-addicted PCa, suggesting therapeutic potential for AR degraders or PP2A modulators in prostate cancer treatment.
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- 2023
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19. Integrative Clinical Genomics of Metastatic Cancer
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Jessica Everett, Xuhong Cao, Jeffrey W. Innis, Rajen Mody, Francis P. Worden, Yi-Mi Wu, David Smith, Javed Siddiqui, Joseph Vijai, Erica Rabban, Moshe Talpaz, Kenneth Offit, Elena M. Stoffel, Daniel F. Hayes, J. Scott Roberts, Ajjai Alva, Chandan Kumar-Sinha, Erin F. Cobain, Robert J. Lonigro, Nithya Ramnath, Marcin Cieślik, Laurence H. Baker, David R. Lucas, Ann F. Schott, Dan R. Robinson, Mark M. Zalupski, Scott A. Tomlins, Victoria M. Raymond, Pankaj Vats, Arul M. Chinnaiyan, Scott M. Schuetze, Lakshmi P. Kunju, and Rashmi Chugh
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Adult ,Male ,0301 basic medicine ,DNA Repair ,Class I Phosphatidylinositol 3-Kinases ,Genetics, Medical ,Ubiquitin-Protein Ligases ,precision medicine ,Genomics ,clinical sequencing ,transcriptome sequencing ,Bioinformatics ,DNA sequencing ,Article ,Metastasis ,whole exome sequencing ,Transcriptome ,03 medical and health sciences ,Germline mutation ,CDKN2A ,Neoplasms ,Exome Sequencing ,Tumor Microenvironment ,medicine ,Cyclin-Dependent Kinase Inhibitor p18 ,PTEN ,Humans ,Neoplasm Metastasis ,Cyclin-Dependent Kinase Inhibitor p16 ,Germ-Line Mutation ,Exome sequencing ,metastatic cancers ,Multidisciplinary ,biology ,PTEN Phosphohydrolase ,High-Throughput Nucleotide Sequencing ,medicine.disease ,3. Good health ,Retinoblastoma Binding Proteins ,030104 developmental biology ,biology.protein ,Female ,Tumor Suppressor Protein p53 - Abstract
SUMMARY Metastasis is the primary cause of cancer-related deaths. While The Cancer Genome Atlas (TCGA) has sequenced primary tumor types obtained from surgical resections, much less comprehensive molecular analysis is available from clinically acquired metastatic cancers. Here, we perform whole exome and transcriptome sequencing of 500 adult patients with metastatic solid tumors of diverse lineage and biopsy site. The most prevalent genes somatically altered in metastatic cancer included TP53, CDKN2A, PTEN, PIK3CA, and RB1. Putative pathogenic germline variants were present in 12.2% of cases of which 75% were related to defects in DNA repair. RNA sequencing complemented DNA sequencing for the identification of gene fusions, pathway activation, and immune profiling. Integrative sequence analysis provides a clinically relevant, multi-dimensional view of the complex molecular landscape and microenvironment of metastatic cancers.
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- 2017
20. Development of Peptidomimetic Inhibitors of the ERG Gene Fusion Product in Prostate Cancer
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Bushra Ateeq, Irfan A. Asangani, Wei Yan, Jean Ching Yi Tien, Xiaoju Wang, Shaomeng Wang, Ingrid J. Apel, Sooryanarayana Varambally, Cynthia Wang, Balabhadrapatruni V. S. K. Chakravarthi, Anton Poliakov, Yuanyuan Qiao, Arul M. Chinnaiyan, Kristin M. Juckette, Sethuramasundaram Pitchiaya, Rui Wang, Hui Jiang, Marcin Cieślik, Xuhong Cao, and Xiaojun Jing
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Male ,0301 basic medicine ,Cancer Research ,genetic structures ,Oncogene Proteins, Fusion ,Peptidomimetic ,Mice, Nude ,Neovascularization, Physiologic ,Antineoplastic Agents ,Chick Embryo ,Biology ,Pharmacology ,Bioinformatics ,medicine.disease_cause ,Fusion gene ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Protein Domains ,Transcriptional Regulator ERG ,Transcription (biology) ,Peptide Library ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Transcription factor ,business.industry ,Prostatic Neoplasms ,DNA-binding domain ,DNA ,Cell Biology ,medicine.disease ,Xenograft Model Antitumor Assays ,eye diseases ,Chromatin ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Product (mathematics) ,Cancer cell ,Cancer research ,sense organs ,Peptidomimetics ,Carcinogenesis ,business ,Erg - Abstract
Transcription factors play a key role in the development of diverse cancers, and therapeutically targeting them has remained a challenge. In prostate cancer, the gene encoding the transcription factor ERG is recurrently rearranged and plays a critical role in prostate oncogenesis. Here, we identified a series of peptides that interact specifically with the DNA binding domain of ERG. ERG inhibitory peptides (EIPs) and derived peptidomimetics bound ERG with high affinity and specificity, leading to proteolytic degradation of the ERG protein. The EIPs attenuated ERG-mediated transcription, chromatin recruitment, protein-protein interactions, cell invasion and proliferation, and tumor growth. Thus, peptidomimetic targeting of transcription factor fusion products may provide a promising therapeutic strategy for prostate cancer as well as other malignancies.
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- 2017
21. VSTM2A Over-expression is a Sensitive and Specific Biomarker for Mucinous Tubular and Spindle Cell Carcinoma (MTSCC) of the Kidney
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Brendan A. Veeneman, Ming Zhou, Javed Siddiqui, Ying-Bei Chen, Pedram Argani, Lisha Wang, Kiril Trpkov, Evita Sadimin, Victor E. Reuter, Jonathan I. Epstein, Adeboye O. Osunkoya, Giovanna A. Giannico, Jin Chen, Hikmat Al-Ahmadie, Hong Xiao, Arul M. Chinnaiyan, Marcin Cieślik, Rohit Mehra, Yuanyuan Qiao, Xuhong Cao, Jesse K. McKenney, Ankur R. Sangoi, Stephanie L. Skala, Pankaj Vats, Saravana M. Dhanasekaran, Yuping Zhang, Xiaoming Wang, Fengyun Su, and Satish K. Tickoo
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0301 basic medicine ,Male ,Pathology ,Chromophobe cell ,0302 clinical medicine ,Renal cell carcinoma ,In Situ Hybridization ,Aged, 80 and over ,Middle Aged ,Adenocarcinoma, Mucinous ,Kidney Neoplasms ,Tumor Burden ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,030220 oncology & carcinogenesis ,Adenocarcinoma ,Biomarker (medicine) ,Female ,Anatomy ,Adult ,medicine.medical_specialty ,Canada ,In situ hybridization ,Biology ,Article ,Pathology and Forensic Medicine ,Diagnosis, Differential ,03 medical and health sciences ,Young Adult ,Predictive Value of Tests ,medicine ,Carcinoma ,Biomarkers, Tumor ,Animals ,Humans ,Carcinoma, Renal Cell ,Aged ,Homeodomain Proteins ,Membrane Proteins ,Reproducibility of Results ,medicine.disease ,Carcinoma, Papillary ,United States ,Rats ,Mucinous tubular and spindle cell carcinoma ,030104 developmental biology ,Loop of Henle ,Surgery ,Neoplasm Grading ,Clear cell ,Transcription Factors - Abstract
Our recent study revealed recurrent chromosomal losses and somatic mutations of genes in the Hippo pathway in mucinous tubular and spindle cell carcinoma (MTSCC). Here, we performed an integrative analysis of 907 renal cell carcinoma (RCC) samples (combined from The Cancer Genome Atlas and in-house studies) and the Knepper dataset of microdissected rat nephrons. We identified VSTM2A and IRX5 as novel cancer- and lineage-specific biomarkers in MTSCC. We then assessed their expression by RNA in situ hybridization (ISH) in 113 tumors, including 33 MTSCC, 40 type 1 papillary RCC (PRCC), 8 type 2 PRCC, 2 unclassified RCC, 15 clear cell RCC, and 15 chromophobe RCC. Sensitivity and specificity were calculated as the area under the receiver operating characteristics curve (AUC). All MTSCC tumors demonstrated moderate to high expression of VSTM2A (mean ISH score = 255). VSTM2A gene expression assessed by RNA sequencing (RNA-seq) strongly correlated with VSTM2A ISH score (r(2) = 0.81, P = 0.00016). The majority of non-MTSCC tumors demonstrated negative or low expression of VSTM2A. IRX5, nominated as a lineage-specific biomarker, showed moderate to high expression in MTSCC tumors (mean ISH score = 140). IRX5 gene expression assessed by RNA-seq strongly correlated with IRX5 ISH score (r(2) = 0.69, P = 0.00291). VSTM2A (AUC: 99.2%) demonstrated better diagnostic efficacy than IRX5 (AUC: 87.5%), and may thus serve as a potential diagnostic marker to distinguish tumors with overlapping histology. Furthermore, our results suggest MTSCC displays an overlapping phenotypic expression pattern with the loop of Henle region of normal nephrons.
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- 2018
22. Proteogenomic insights into the biology and treatment of HPV-negative head and neck squamous cell carcinoma
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Tara Skelly, Wen Jiang, Zhen Zhang, Anupriya Agarwal, Amy M. Perou, Olga Potapova, Christopher R. Kinsinger, Matthew A. Wyczalkowski, David J. Clark, Shuang Cai, Felipe da Veiga Leprevost, Linda Hannick, Chen Huang, Paul D. Piehowski, John McGee, Marcin J. Domagalski, Dmitris Placantonakis, Jianbo Pan, Dana R. Valley, Zhiao Shi, Hui Yin Chang, Karen A. Ketchum, Charles A. Goldthwaite, Małgorzata Wierzbicka, Karsten Krug, Yvonne Shutack, Sara R. Savage, Matthew L. Anderson, Alyssa Charamut, Chandan Kumar-Sinha, Sanford P. Markey, Ratna R. Thangudu, Weiping Ma, Oliver F. Bathe, Antonio Colaprico, Yuxing Liao, Eric E. Schadt, Tomasz Czernicki, Seungyeul Yoo, Xi Chen, Stacey Gabriel, Karl R. Clauser, Daniel C. Rohrer, Uma Borate, Uma Velvulou, Larisa Polonskaya, M. Harry Kane, Dmitry M. Avtonomov, Boris Reva, Jacob J. Day, Barbara Hindenach, Matthew J. Ellis, Katherine A. Hoadley, Emek Demir, Rebecca I. Montgomery, Ewa P. Malc, Fengchao Yu, Lijun Yao, Maciej Wiznerowicz, Annette Marrero-Oliveras, Wojciech Szopa, Sailaja Mareedu, Galen Hostetter, Liqun Qi, Hui Zhang, Yige Wu, David N. Hayes, Shankha Satpathy, Corbin D. Jones, Michael J. Birrer, Xinpei Yi, Nathan Edwards, Fei Ding, Jiang Qian, Ning Qu, Alicia Francis, Daniel Cui Zhou, Jakub Stawicki, Bing Zhang, Rodrigo Vargas Eguez, Tao Liu, Dave Tabor, Maureen Dyer, Brian J. Druker, Gilbert S. Omenn, Azra Krek, Meenakshi Anurag, Melissa Borucki, Mathangi Thiagarajan, Shirley Tsang, Shakti Ramkissoon, Alexey I. Nesvizhskii, Li Ding, Lyubomir Valkov Vasilev, Yifat Geffen, James Suh, Tatiana S. Ermakova, Kakhaber Zaalishvili, Adel K. El-Naggar, Ki Sung Um, Ana I. Robles, Wen-Wei Liang, Richard D. Smith, Pei Wang, Emily S. Boja, Anna Calinawan, Yingwei Hu, Jiayi Ji, Renata Ferrarotto, Hongwei Liu, Jonathan T. Lei, Ramani B. Kothadia, Yize Li, Chelsea J. Newton, Anna Malovannaya, Steven A. Carr, Sandra Cerda, Yuriy Zakhartsev, Stephanie De Young, Eric J. Jaehnig, Peter B. McGarvey, Yan Shi, David I. Heiman, Joseph C. Dort, Karin D. Rodland, Lili Blumenberg, Michael A. Gillette, Piotr A. Mieczkowski, Pankaj Vats, Chet Birger, Yongchao Dou, David Fenyö, Saravana M. Dhanasekaran, Pushpa Hariharan, Eunkyung An, Jeffrey R. Whiteaker, George Miles, Jan Lubinski, Shayan C. Avanessian, Samuel H. Payne, Amanda G. Paulovich, Dmitry Rykunov, Lyudmila Petrenko, Martin Hyrcza, Guo Ci Teo, Alissa M. Weaver, D. R. Mani, Houston Culpepper, Meghan C. Burke, Daniel W. Chan, Bo Wen, Nicollette Maunganidze, Elie Traer, Darlene Tansil, Simona Migliozzi, Luciano Garofano, Qing Kay Li, Donghui Tan, Lori J. Sokoll, Mehdi Mesri, Karna Robinson, Fulvio D'Angelo, Kimberly Elburn, Alexander R. Pico, Umut Ozbek, Michael Schnaubelt, Gad Getz, Francesca Petralia, Andrew G. Sikora, Kai Li, Elena V. Ponomareva, Arul M. Chinnaiyan, Robert Zelt, Jun Zhu, Midie Xu, Dimitar Dimitrov Pazardzhikliev, Negin Vatanian, Grace Zhao, Thomas F. Westbrook, Kyung-Cho Cho, Yuefan Wang, Jason E. McDermott, Jeffrey W. Tyner, William Bocik, Shilpi Singh, Stephen E. Stein, Nancy Roche, Alicia Karz, Shannon Richey, Tara Hiltke, Michael Vernon, Lijun Chen, Henry Rodriguez, Xiaoyu Song, Elizabeth R. Duffy, Lin S. Chen, Liwei Cao, Shrabanti Chowdhury, Marcin Cieślik, Michael C. Wendl, Scott D. Jewell, and Cristina E. Tognon
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Adult ,Male ,Proteomics ,0301 basic medicine ,Cancer Research ,medicine.medical_treatment ,Cell ,Biology ,Article ,Young Adult ,03 medical and health sciences ,Antineoplastic Agents, Immunological ,0302 clinical medicine ,Cyclin-dependent kinase ,medicine ,Humans ,Aged ,Proteogenomics ,Aged, 80 and over ,Squamous Cell Carcinoma of Head and Neck ,Papillomavirus Infections ,Phosphoproteomics ,Immunotherapy ,Middle Aged ,medicine.disease ,Head and neck squamous-cell carcinoma ,Immune checkpoint ,ErbB Receptors ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Female - Abstract
We present a proteogenomic study of 108 human papilloma virus (HPV)-negative head and neck squamous cell carcinomas (HNSCCs). Proteomic analysis systematically catalogs HNSCC-associated proteins and phosphosites, prioritizes copy number drivers, and highlights an oncogenic role for RNA processing genes. Proteomic investigation of mutual exclusivity between FAT1 truncating mutations and 11q13.3 amplifications reveals dysregulated actin dynamics as a common functional consequence. Phosphoproteomics characterizes two modes of EGFR activation, suggesting a new strategy to stratify HNSCCs based on EGFR ligand abundance for effective treatment with inhibitory EGFR monoclonal antibodies. Widespread deletion of immune modulatory genes accounts for low immune infiltration in immune-cold tumors, whereas concordant upregulation of multiple immune checkpoint proteins may underlie resistance to anti-programmed cell death protein 1 monotherapy in immune-hot tumors. Multi-omic analysis identifies three molecular subtypes with high potential for treatment with CDK inhibitors, anti-EGFR antibody therapy, and immunotherapy, respectively. Altogether, proteogenomics provides a systematic framework to inform HNSCC biology and treatment.
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- 2021
23. Integrated Proteogenomic Characterization across Major Histological Types of Pediatric Brain Cancer
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Matthew E. Monroe, Saravana M. Dhanasekaran, Brian R. Rood, Zeynep H. Gümüş, Jena Lilly, Samuel G. Winebrake, Richard G. Ivey, William Bocik, Mahdi Sarmady, Alicia Francis, Lamiya Tauhid, Nathan Edwards, Lizabeth Katsnelson, Rui Zhao, Matilda Broberg, Jo Lynne Rokita, Mateusz Koptyra, Henry Rodriguez, Cassie Kline, Shrabanti Chowdhury, Nicole Tignor, Ying Wang, Christopher R. Kinsinger, Antonio Colaprico, Amanda G. Paulovich, Weiping Ma, Emily S. Boja, Tara Hiltke, Sabine Mueller, Liang-Bo Wang, Javad Nazarian, Marcin J. Domagalski, Karl K. Weitz, Jessica B. Foster, Robert Lober, Carina A. Leonard, Bo Zhang, Gerald A. Grant, Anna Calinawan, Gonzalo Lopez, Shuang Cai, Joanna J. Phillips, Guo Ci Teo, July E. Palma, Felipe da Veiga Leprevost, Yiran Guo, Angela Waanders, Xiaoyu Song, Li Ding, Allison Heath, Steven P. Gygi, Rosalie K. Chu, Vasileios Stathias, Bailey Farrow, Oren J. Becher, Dmitry Rykunov, Nithin D. Adappa, Ron Firestein, Adam C. Resnick, Marcin Cieślik, Jennifer Mason, D. R. Mani, Selim Kalayci, Boris Reva, Antonio Iavarone, MacIntosh Cornwell, Uliana J. Voytovich, Gabrielle S. Stone, Miguel A. Brown, Jacob J. Kennedy, Tao Liu, Ronald J. Moore, Emily Kawaler, Eric H. Raabe, Marina A. Gritsenko, Valerie Baubet, Francesca Petralia, Maciej Wiznerowicz, Olena Morozova Vaske, Eric E. Schadt, Ian F. Pollack, Arul M. Chinnaiyan, Meghan Connors, Jason E. Cain, Lei Zhao, Matthew A. Wyczalkowski, Nalin Gupta, Bing Zhang, Jiayi Ji, Marilyn M. Li, Samuel Rivero-Hinojosa, Mariarita Santi, Wenke Liu, John Szpyt, Brian Ennis, Alexey I. Nesvizhskii, Joshua M. Wang, Jeffrey P. Greenfield, Sanjukta Guha Thakurta, Hui Yin Chang, Peter B. McGarvey, Xi Chen, Karen A. Ketchum, Stephan C. Schürer, Sarah Leary, Lili Blumenberg, Matthew J. Ellis, Pei Wang, Anna Maria Buccoliero, Karsten Krug, Chiara Caporalini, Gad Getz, David E. Kram, Pichai Raman, Eric M. Jackson, James N. Palmer, Mehdi Mesri, Kelly V. Ruggles, Chunde Li, Jun Zhu, Sonia Partap, Jeffrey R. Whiteaker, Mirko Scagnet, Krutika S. Gaonkar, Azra Krek, Allison M. Morgan, Tatiana Omelchenko, Richard D. Smith, Elizabeth Appert, Karin D. Rodland, Derek Hanson, Phillip B. Storm, Jamie Moon, Vladislav A. Petyuk, Nathan Young, Travis D. Lorentzen, David Fenyö, Angela N. Viaene, Seungyeul Yoo, Yuankun Zhu, Nicholas A Vitanza, Toan Le, Tatiana Patton, and Ana I. Robles
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DNA Copy Number Variations ,Computational biology ,Biology ,Proteomics ,Article ,General Biochemistry, Genetics and Molecular Biology ,Ganglioglioma ,03 medical and health sciences ,Lymphocytes, Tumor-Infiltrating ,0302 clinical medicine ,Glioma ,medicine ,Humans ,Gene Regulatory Networks ,RNA, Messenger ,Copy-number variation ,Phosphorylation ,Child ,Proteogenomics ,030304 developmental biology ,Medulloblastoma ,0303 health sciences ,Brain Neoplasms ,Genome, Human ,Phosphoproteomics ,Phosphoproteins ,medicine.disease ,Gene Expression Regulation, Neoplastic ,Mutation ,Atypical teratoid rhabdoid tumor ,Neoplasm Grading ,Neoplasm Recurrence, Local ,Transcriptome ,030217 neurology & neurosurgery - Abstract
We report a comprehensive proteogenomics analysis, including whole-genome sequencing, RNA sequencing, and proteomics and phosphoproteomics profiling, of 218 tumors across 7 histological types of childhood brain cancer: low-grade glioma (n = 93), ependymoma (32), high-grade glioma (25), medulloblastoma (22), ganglioglioma (18), craniopharyngioma (16), and atypical teratoid rhabdoid tumor (12). Proteomics data identify common biological themes that span histological boundaries, suggesting that treatments used for one histological type may be applied effectively to other tumors sharing similar proteomics features. Immune landscape characterization reveals diverse tumor microenvironments across and within diagnoses. Proteomics data further reveal functional effects of somatic mutations and copy number variations (CNVs) not evident in transcriptomics data. Kinase-substrate association and co-expression network analysis identify important biological mechanisms of tumorigenesis. This is the first large-scale proteogenomics analysis across traditional histological boundaries to uncover foundational pediatric brain tumor biology and inform rational treatment selection.
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- 2020
24. Unraveling the glycosylated immunopeptidome with HLA-Glyco
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Georges Bedran, Daniel A. Polasky, Yi Hsiao, Fengchao Yu, Felipe da Veiga Leprevost, Javier A. Alfaro, Marcin Cieslik, and Alexey I. Nesvizhskii
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Science - Abstract
Abstract Recent interest in targeted therapies has been sparked by the study of MHC-associated peptides (MAPs) that undergo post-translational modifications (PTMs), particularly glycosylation. In this study, we introduce a fast computational workflow that merges the MSFragger-Glyco search algorithm with a false discovery rate control for glycopeptide analysis from mass spectrometry-based immunopeptidome data. By analyzing eight large-scale publicly available studies, we find that glycosylated MAPs are predominantly presented by MHC class II. Here, we present HLA-Glyco, a comprehensive resource containing over 3,400 human leukocyte antigen (HLA) class II N-glycopeptides from 1,049 distinct protein glycosylation sites. This resource provides valuable insights, including high levels of truncated glycans, conserved HLA-binding cores, and differences in glycosylation positional specificity between HLA allele groups. We integrate the workflow within the FragPipe computational platform and provide HLA-Glyco as a free web resource. Overall, our work provides a valuable tool and resource to aid the nascent field of glyco-immunopeptidomics.
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- 2023
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25. Identification and Validation of PCAT14 as Prognostic Biomarker in Prostate Cancer
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Yashar S. Niknafs, Marcin Cieślik, Arul M. Chinnaiyan, Xiaojun Jing, Bhavna Malik, Lanbo Xiao, Rohit Mehra, Bui Huynh-Hoa, Xiang Zhang, Xuhong Cao, Rohit Malik, Felix Y. Feng, Edward M. Schaeffer, Susan M. Freier, Shuling Guo, Saravana M. Dhanasekaran, Sudhanshu Shukla, Javed Siddiqui, and Ashley E. Ross
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0301 basic medicine ,PCA3 ,Cancer Research ,Cancer ,Disease ,In situ hybridization ,Biology ,Bioinformatics ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,lcsh:RC254-282 ,3. Good health ,Gene expression profiling ,Management of prostate cancer ,03 medical and health sciences ,Prostate cancer ,030104 developmental biology ,Cancer research ,medicine ,Gene - Abstract
Rapid advances in the discovery of long noncoding RNAs (lncRNAs) have identified lineage- and cancer-specific biomarkers that may be relevant in the clinical management of prostate cancer (PCa). Here we assembled and analyzed a large RNA-seq dataset, from 585 patient samples, including benign prostate tissue and both localized and metastatic PCa to discover and validate differentially expressed genes associated with disease aggressiveness. We performed Sample Set Enrichment Analysis (SSEA) and identified genes associated with low versus high Gleason score in the RNA-seq database. Comparing Gleason 6 versus 9+ PCa samples, we identified 99 differentially expressed genes with variable association to Gleason grade as well as robust expression in prostate cancer. The top-ranked novel lncRNA PCAT14, exhibits both cancer and lineage specificity. On multivariate analysis, low PCAT14 expression independently predicts for BPFS ( P =.00126), PSS ( P =.0385), and MFS ( P =.000609), with trends for OS as well ( P =.056). An RNA in-situ hybridization (ISH) assay for PCAT14 distinguished benign vs malignant cases, as well as high vs low Gleason disease. PCAT14 is transcriptionally regulated by AR, and endogenous PCAT14 overexpression suppresses cell invasion. Thus, Using RNA-sequencing data we identify PCAT14, a novel prostate cancer and lineage-specific lncRNA. PCAT14 is highly expressed in low grade disease and loss of PCAT14 predicts for disease aggressiveness and recurrence.
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- 2016
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26. Characterizing the Therapeutic Potential of a Potent BET Degrader in Merkel Cell Carcinoma
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Jonathan Gurkan, Fengyun Su, Kristin M. Juckette, Rohit Malik, Marcin Cieślik, Andrzej A. Dlugosz, Rui Wang, Xuhong Cao, Monique Verhaegen, Xiaojun Jing, Bing Zhou, Sahr Yazdani, Mishaal Yazdani, Jean Tien, Arul M. Chinnaiyan, Jae Eun Choi, Yuping Wang, Paul W. Harms, Ingrid J. Apel, Doris Mangelberger, and Shaomeng Wang
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0301 basic medicine ,Cancer Research ,Original article ,BET, bromodomain and extra terminal domain ,Skin Neoplasms ,MCPyV, Merkel cell polyomavirus ,Merkel cell polyomavirus ,chemical and pharmacologic phenomena ,lcsh:RC254-282 ,BET inhibitor ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,medicine ,Humans ,Hox gene ,Antigens, Viral, Tumor ,Gene ,Polyomavirus Infections ,biology ,Dose-Response Relationship, Drug ,Merkel cell carcinoma ,Chemistry ,Gene Expression Profiling ,Cell Cycle ,Genes, Homeobox ,food and beverages ,Proteins ,hemic and immune systems ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,biology.organism_classification ,Cell Cycle Gene ,Small molecule ,3. Good health ,Carcinoma, Merkel Cell ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Cell culture ,030220 oncology & carcinogenesis ,Proteolysis ,Cancer research ,Acetanilides ,Transcriptome ,Heterocyclic Compounds, 3-Ring - Abstract
Studies on the efficacy of small molecule inhibitors in Merkel cell carcinoma (MCC) have been limited and largely inconclusive. In this study, we investigated the therapeutic potential of a potent BET degrader, BETd-246, in the treatment of MCC. We found that MCC cell lines were significantly more sensitive to BETd-246 than to BET inhibitor treatment. Therapeutic targeting of BET proteins resulted in a loss of “MCC signature” genes but not MYC expression as previously described irrespective of Merkel cell polyomavirus (MCPyV) status. In MCPyV+ MCC cells, BETd-246 alone suppressed downstream targets in the MCPyV-LT Ag axis. We also found enrichment of HOX and cell cycle genes in MCPyV− MCC cell lines that were intrinsically resistant to BETd-246. Our findings uncover a requirement for BET proteins in maintaining MCC lineage identity and point to the potential utility of BET degraders for treating MCC.
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- 2018
27. Competing for enhancers: PVT1 fine-tunes MYC expression
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Arul M. Chinnaiyan, Marcin Cieślik, and Abhijit Parolia
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0301 basic medicine ,Transcription, Genetic ,Carcinogenesis ,Genes, myc ,Breast Neoplasms ,Computational biology ,Biology ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,Text mining ,Mice, Inbred NOD ,Neoplasms ,Cell Line, Tumor ,medicine ,Neoplasm ,Animals ,Humans ,Enhancer ,Promoter Regions, Genetic ,Molecular Biology ,Gene ,Cell Proliferation ,business.industry ,Gene Expression Profiling ,RNA ,Cell Biology ,DNA, Neoplasm ,medicine.disease ,Research Highlight ,Chromatin ,PVT1 ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Cell Transformation, Neoplastic ,Enhancer Elements, Genetic ,chemistry ,Mutation ,Female ,RNA, Long Noncoding ,CRISPR-Cas Systems ,business ,DNA ,Neoplasm Transplantation - Abstract
Noncoding mutations in cancer genomes are frequent but challenging to interpret. PVT1 encodes an oncogenic lncRNA, but recurrent translocations and deletions in human cancers suggest alternative mechanisms. Here, we show that the PVT1 promoter has a tumor-suppressor function that is independent of PVT1 lncRNA. CRISPR interference of PVT1 promoter enhances breast cancer cell competition and growth in vivo. The promoters of the PVT1 and the MYC oncogenes, located 55 kb apart on chromosome 8q24, compete for engagement with four intragenic enhancers in the PVT1 locus, thereby allowing the PVT1 promoter to regulate pause release of MYC transcription. PVT1 undergoes developmentally regulated monoallelic expression, and the PVT1 promoter inhibits MYC expression only from the same chromosome via promoter competition. Cancer genome sequencing identifies recurrent mutations encompassing the human PVT1 promoter, and genome editing verified that PVT1 promoter mutation promotes cancer cell growth. These results highlight regulatory sequences of lncRNA genes as potential disease-associated DNA elements.
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- 2018
28. Common molecular features of H3K27M DMGs and PFA ependymomas map to hindbrain developmental pathways
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Matthew Pun, Drew Pratt, Patricia R. Nano, Piyush K. Joshi, Li Jiang, Bernhard Englinger, Arvind Rao, Marcin Cieslik, Arul M. Chinnaiyan, Kenneth Aldape, Stefan Pfister, Mariella G. Filbin, Aparna Bhaduri, and Sriram Venneti
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Cancer ,Chromatin biology ,Onco-histones ,Pediatric tumors ,Brain development ,Neuro-oncology ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Globally decreased histone 3, lysine 27 tri-methylation (H3K27me3) is a hallmark of H3K27-altered diffuse midline gliomas (DMGs) and group-A posterior fossa ependymomas (PFAs). H3K27-altered DMGs are largely characterized by lysine-to-methionine mutations in histone 3 at position 27 (H3K27M). Most PFAs overexpress EZH inhibitory protein (EZHIP), which possesses a region of similarity to the mutant H3K27M. Both H3K27M and EZHIP inhibit the function of the polycomb repressive complex 2 (PRC2) responsible for H3K27me3 deposition. These tumors often arise in neighboring regions of the brainstem and posterior fossa. In rare cases PFAs harbor H3K27M mutations, and DMGs overexpress EZHIP. These findings together raise the possibility that certain cell populations in the developing hindbrain/posterior fossa are especially sensitive to modulation of H3K27me3 states. We identified shared molecular features by comparing genomic, bulk transcriptomic, chromatin-based profiles, and single-cell RNA-sequencing (scRNA-seq) data from the two tumor classes. Our approach demonstrated that 1q gain, a key biomarker in PFAs, is prognostic in H3.1K27M, but not H3.3K27M gliomas. Conversely, Activin A Receptor Type 1 (ACVR1), which is associated with mutations in H3.1K27M gliomas, is overexpressed in a subset of PFAs with poor outcome. Despite diffuse H3K27me3 reduction, previous work shows that both tumors maintain genomic H3K27me3 deposition at select sites. We demonstrate heterogeneity in shared patterns of residual H3K27me3 for both tumors that largely segregated with inferred anatomic tumor origins and progenitor populations of tumor cells. In contrast, analysis of genes linked to H3K27 acetylation (H3K27ac)-marked enhancers showed higher expression in astrocytic-like tumor cells. Finally, common H3K27me3-marked genes mapped closely to expression patterns in the human developing hindbrain. Overall, our data demonstrate developmentally relevant molecular similarities between PFAs and H3K27M DMGs and support the overall hypothesis that deregulated mechanisms of hindbrain development are central to the biology of both tumors.
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- 2023
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29. Targeting the MLL complex in castration-resistant prostate cancer
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John R. Prensner, Yashar S. Niknafs, Arul M. Chinnaiyan, Nallasivam Palanisamy, Alexey I. Nesvizhskii, Yi-Mi Wu, Dattatreya Mellacheruvu, Xiaojun Jing, Matthew K. Iyer, Pranathi Meda Krishnamurthy, Rohit Malik, Lakshmi P. Kunju, Yuanyuan Qiao, Saravana M. Dhanasekaran, Rachell Stender, Tomasz Cierpicki, Anastasia K. Yocum, Dmitry Borkin, Xuhong Cao, Felix Y. Feng, Amjad Khan, Marcin Cieślik, Xia Jiang, Jolanta Grembecka, Xiaoju Wang, June Escara-Wilke, and Irfan A. Asangani
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medicine.drug_class ,Cancer ,General Medicine ,Biology ,Androgen ,medicine.disease ,Bioinformatics ,General Biochemistry, Genetics and Molecular Biology ,Androgen receptor ,Leukemia ,Prostate cancer ,hemic and lymphatic diseases ,medicine ,Cancer research ,Myeloid-Lymphoid Leukemia Protein ,Neoplasm ,Signal transduction ,neoplasms - Abstract
Resistance to androgen deprivation therapies and increased androgen receptor (AR) activity are major drivers of castration-resistant prostate cancer (CRPC). Although prior work has focused on targeting AR directly, co-activators of AR signaling, which may represent new therapeutic targets, are relatively underexplored. Here we demonstrate that the mixed-lineage leukemia protein (MLL) complex, a well-known driver of MLL fusion-positive leukemia, acts as a co-activator of AR signaling. AR directly interacts with the MLL complex via the menin-MLL subunit. Menin expression is higher in CRPC than in both hormone-naive prostate cancer and benign prostate tissue, and high menin expression correlates with poor overall survival of individuals diagnosed with prostate cancer. Treatment with a small-molecule inhibitor of menin-MLL interaction blocks AR signaling and inhibits the growth of castration-resistant tumors in vivo in mice. Taken together, this work identifies the MLL complex as a crucial co-activator of AR and a potential therapeutic target in advanced prostate cancer.
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- 2015
30. Distinct mutational processes shape selection of MHC class I and class II mutations across primary and metastatic tumors
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Michael B. Mumphrey, Noshad Hosseini, Abhijit Parolia, Jie Geng, Weiping Zou, Malini Raghavan, Arul Chinnaiyan, and Marcin Cieslik
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CP: Cancer ,CP: Immunology ,Biology (General) ,QH301-705.5 - Abstract
Summary: Disruption of antigen presentation via loss of major histocompatibility complex (MHC) expression is a strategy whereby cancer cells escape immune surveillance and develop resistance to immunotherapy. Here, we develop the personalized genomics algorithm Hapster and accurately call somatic mutations within the MHC genes of 10,001 primary and 2,199 metastatic tumors, creating a catalog of 1,663 non-synonymous mutations that provide key insights into MHC mutagenesis. We find that MHC class I genes are among the most frequently mutated genes in both primary and metastatic tumors, while MHC class II mutations are more restricted. Recurrent deleterious mutations are found within haplotype- and cancer-type-specific hotspots associated with distinct mutational processes. Functional classification of MHC residues reveals significant positive selection for mutations disruptive to the B2M, peptide, and T cell binding interfaces, as well as to MHC chaperones.
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- 2023
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31. Abstract 4091: Evaluating the efficacy of a STING agonist in a murine model of prostate cancer
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Jonathan Gurkan, Jae Eun Choi, Jean Tien, Marcin Cieślik, Luigi Franchi, and Arul M. Chinnaiyan
- Subjects
Cancer Research ,Oncology - Abstract
Despite the promise of checkpoint inhibitor therapy, prostate cancer has remained resistant to this treatment. Innate immune agonists, however, have been shown to have anti-tumor effects in various cancer types, such as melanoma and colon cancer, and have been nominated to be used in combination with approved anti-PD1/PD-L1 drugs. For instance, STING agonist + anti-PD-1 combination therapy has been demonstrated in a syngeneic mouse model of melanoma. Other innate immune agonists, such as TLR7/8 and TLR9 have also been shown to have potential anti-tumor effects. We hypothesized that innate immune agonists may be effective in the MycCaP syngeneic mouse model of prostate cancer. To compare the efficacy of three innate agonists targeting the STING (3’3’ cGAMP), TLR7/8 (CL097), and TLR9 (ODN2395) pathways, FVB mice were first injected bilaterally with MycCaP subcutaneous tumors. Upon establishment of tumors, mice were administered 3 doses of a single-sided intratumoral injection of each drug. The injected tumors had responses of 50% (6/12), 23% (3/13), and 8% (1/13) for the STING, TLR7/8 and, TLR8 agonists, respectively. Contralateral tumors showed no significant regression. Published data have reported inherent resistance of MycCaP tumors to anti-PD-1 treatment in vivo. Given our results, we hypothesize that the addition of a STING agonist could enhance efficacy of anti-PD-1 therapy in this model. Mice with MycCaP tumors were administered anti-PD1 alone (n=10) or in combination with bilateral injections of the STING agonist (n=14). Combined therapy resulted in significant reduction in tumor size (71%) compared to anti-PD1 alone (9%). Additionally, there was a significant increase in the Ifnb1 (p=.04), Ifng (p=.008), Tnf-α (p=.006), IRF3 (p=.003) and II6 (p Citation Format: Jonathan Gurkan, Jae Eun Choi, Jean Tien, Marcin Cieślik, Luigi Franchi, Arul M. Chinnaiyan. Evaluating the efficacy of a STING agonist in a murine model of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4091.
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- 2019
32. Bubble-seq analysis of the human genome reveals distinct chromatin-mediated mechanisms for regulating early- and late-firing origins
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Joyce L. Hamlin, Larry D. Mesner, Stefan Bekiranov, Veena Valsakumar, Rebecca R. Pickin, and Marcin Cieślik
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Epigenomics ,Transcriptional Activation ,Transcription, Genetic ,Euchromatin ,DNA Replication Timing ,Heterochromatin ,Molecular Sequence Data ,Replication Origin ,Biology ,Cell Line, Tumor ,Genetics ,Deoxyribonuclease I ,Humans ,Genetics (clinical) ,Replication timing ,Models, Genetic ,Genome, Human ,Research ,Sequence Analysis, DNA ,Chromatin ,Genetic Loci ,Origin recognition complex ,Human genome ,HeLa Cells - Abstract
We have devised a method for isolating virtually pure and comprehensive libraries of restriction fragments that contained replication initiation sites (bubbles) in vivo. We have now sequenced and mapped the bubble-containing fragments from GM06990, a near-normal EBV-transformed lymphoblastoid cell line, and have compared origin distributions with a comprehensive replication timing study recently published for this cell line. We find that early-firing origins, which represent ∼32% of all origins, overwhelmingly represent zones, associate only marginally with active transcription units, are localized within large domains of open chromatin, and are significantly associated with DNase I hypersensitivity. Origin “density” falls from early- to mid-S-phase, but rises again in late S-phase to levels only 17% lower than in early S-phase. Unexpectedly, late origin density calculated on the 1-Mb scale increases as a function of increasing chromatin compaction. Furthermore, the median efficiency of origins in late-replicating, heterochromatic domains is only 25% lower than in early-replicating euchromatic loci. Thus, the activation of early- and late-firing origins must be regulated by quintessentially different mechanisms. The aggregate data can be unified into a model in which initiation site selection is driven almost entirely by epigenetic factors that fashion both the long-range and local chromatin environments, with underlying DNA sequence and local transcriptional activity playing only minor roles. Importantly, the comprehensive origin map we have prepared for GM06990 overlaps moderately well with origin maps recently reported for the genomes of four different human cell lines based on the distributions of small nascent strands.
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- 2013
33. Analysis of the Tumor Immune Microenvironment (TIME) in Clear Cell Renal Cell Carcinoma (ccRCC) Reveals an M0 Macrophage-Enriched Subtype: An Exploration of Prognostic and Biological Characteristics of This Immune Phenotype
- Author
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Mark Farha, Srinivas Nallandhighal, Randy Vince, Brittney Cotta, Judith Stangl-Kremser, Daniel Triner, Todd M. Morgan, Ganesh S. Palapattu, Marcin Cieslik, Ulka Vaishampayan, Aaron M. Udager, and Simpa S. Salami
- Subjects
clear cell renal cell carcinoma (ccRCC) ,tumor immune microenvironment (TIME) ,macrophages ,genomics ,immune checkpoint blockade ,biomarkers ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
There is a need to optimize the treatment of clear cell renal cell carcinoma (ccRCC) patients at high recurrence risk after nephrectomy. We sought to elucidate the tumor immune microenvironment (TIME) of localized ccRCC and understand the prognostic and predictive characteristics of certain features. The discovery cohort was clinically localized patients in the TCGA-Kidney Renal Clear Cell Carcinoma (KIRC) project (n = 382). We identified an M0 macrophage-enriched cluster (n = 25) in the TCGA-KIRC cohort. This cluster’s median progression-free survival (PFS) and overall survival (OS) were 40.4 and 45.3 months, respectively, but this was not reached in the others (p = 0.0003 and n = 9) with shorter PFS (p = 0.0006) was also identified in the Clinical Proteomics Tumor Analysis Consortium (CPTAC) cohort (n = 94). Through this characterization of the TIME in ccRCC, a cluster of patients defined by enrichment in M0 macrophages was identified that demonstrated poor prognosis and lower predicted ICB response. Pending further validation, this signature can identify localized ccRCC patients at high risk of recurrence after nephrectomy and who may require therapeutic approaches beyond ICB monotherapy.
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- 2023
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34. MicroRNA-101 regulated transcriptional modulator SUB1 plays a role in prostate cancer
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Moloy T. Goswami, A. M. Chinnaiyan, Shannon Carskadon, Stephanie Daignault, Sumit Agarwal, Nallasivam Palanisamy, Sooryanarayana Varambally, Balabhadrapatruni V. S. K. Chakravarthi, Marcin Cieślik, Xiaojun Jing, Darshan S. Chandrashekar, L.P. Kunju, Alyncia D. Robinson, Javed Siddiqui, and Satya S. Pathi
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0301 basic medicine ,Male ,Cancer Research ,Biology ,medicine.disease_cause ,Metastasis ,03 medical and health sciences ,Prostate cancer ,Mice ,Genetics ,medicine ,Animals ,Humans ,Molecular Biology ,Transcription factor ,Cell Proliferation ,Regulation of gene expression ,EZH2 ,Prostatic Neoplasms ,medicine.disease ,DNA-Binding Proteins ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,030104 developmental biology ,Gene Knockdown Techniques ,Cancer cell ,Cancer research ,Heterografts ,Proteasome maturation protein ,Original Article ,Carcinogenesis ,Transcription Factors - Abstract
MicroRNA-101, a tumor suppressor microRNA (miR), is often downregulated in cancer and is known to target multiple oncogenes. Some of the genes that are negatively regulated by miR-101 expression include histone methyltransferase EZH2 (enhancer of zeste homolog 2), COX2 (cyclooxygenase-2), POMP (proteasome maturation protein), CERS6, STMN1, MCL-1 and ROCK2, among others. In the present study, we show that miR-101 targets transcriptional coactivator SUB1 homolog (Saccharomyces cerevisiae)/PC4 (positive cofactor 4) and regulates its expression. SUB1 is known to have diverse role in vital cell processes such as DNA replication, repair and heterochromatinization. SUB1 is known to modulate transcription and acts as a mediator between the upstream activators and general transcription machinery. Expression profiling in several cancers revealed SUB1 overexpression, suggesting a potential role in tumorigenesis. However, detailed regulation and function of SUB1 has not been elucidated. In this study, we show elevated expression of SUB1 in aggressive prostate cancer. Knockdown of SUB1 in prostate cancer cells resulted in reduced cell proliferation, invasion and migration in vitro, and tumor growth and metastasis in vivo. Gene expression analyses coupled with chromatin immunoprecipitation revealed that SUB1 binds to the promoter regions of several oncogenes such as PLK1 (Polo-like kinase 1), C-MYC, serine-threonine kinase BUB1B and regulates their expression. Additionally, we observed SUB1 downregulated CDKN1B expression. PLK1 knockdown or use of PLK1 inhibitor can mitigate oncogenic function of SUB1 in benign prostate cancer cells. Thus, our study suggests that miR-101 loss results in increased SUB1 expression and subsequent activation of known oncogenes driving prostate cancer progression and metastasis. This study therefore demonstrates functional role of SUB1 in prostate cancer, and identifies its regulation and potential downstream therapeutic targets of SUB1 in prostate cancer.
- Published
- 2016
35. Genome-wide predictors of NF-κB recruitment and transcriptional activity
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Marcin Cieślik and Stefan Bekiranov
- Subjects
Research ,Promoter ,Computational biology ,Biology ,Bioinformatics ,Biochemistry ,Chromatin ,Computer Science Applications ,Computational Mathematics ,Histone ,Cistrome ,Computational Theory and Mathematics ,DNA methylation ,biology.protein ,Transcriptional regulation ,Genetics ,Epigenetics ,Transcription factor ,Molecular Biology - Abstract
Background Inducible transcription factors (TFs) mediate transcriptional responses to environmental cues. In response to multiple inflammatory signals active NF-κB dimers enter the nucleus and trigger cell-type-, and stimulus-specific transcriptional programs. Although much is known about NF-κB inducing pathways and about locus-specific mechanisms of transcriptional control, it is poorly understood how the pre-existing chromatin landscape determines NF-κB target selection and activation. Specifically, it is not known which epigenetic marks and pre-bound TFs serve genome-wide as positive (negative) cues for active NF-κB. Results We applied multivariate and combinatorial data mining techniques on a comprehensive dataset of DNA methylation, DNase I hypersensitivity, eight epigenetic marks, and 34 TFs to arrive at genome-wide patterns that predict NF-κB binding. Strikingly, we observed NF-κB recruitment to accessible and nucleosome-bound sites. Within nucleosomal DNA NF-κB binding was primed by H3K4me1 and H2A.Z, but also hyper-methylated DNA outside of promoters and CpG-islands. Many of these predictors showed combinatorial cooperativity and statistically significant interactions. Recruitment to pre-accessible sites was more frequent and influenced by chromatin-associated TFs. We observed that specific TF-combinations are greatly enriched for (or depleted of) NF-κB binding events. Conclusions We provide evidence of NF-κB binding within genomic regions that lack classical marks of activity. These pioneer binding events are relatively often associated with transcriptional regulation. Further, our predictive models indicate that specific combinations of epigenetic marks and transcription factors predetermine the NF-κB cistrome, supporting the feasibility of using statistical approaches to identify “histone codes”. Electronic supplementary material The online version of this article (doi:10.1186/s13040-015-0071-3) contains supplementary material, which is available to authorized users.
- Published
- 2015
36. Abstract 2458: The androgen receptor-regulated lncRNA landscape reveals a role for ARlnc1 in prostate cancer progression
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Mats Ljungman, Lisha Wang, Rohit Malik, Yuanyuan Qiao, Yajia Zhang, Jean C. Tien, Marcin Cieślik, Yashar S. Niknafs, Xuhong Cao, Yasuyuki Hosono, Shuling Guo, Hui Jiang, Sethuramasundaram Pitchiaya, Rohit Mehra, and Arul M. Chinnaiyan
- Subjects
0301 basic medicine ,Untranslated region ,Cancer Research ,Gene knockdown ,medicine.drug_class ,Cancer ,Biology ,Androgen ,medicine.disease ,Androgen receptor ,03 medical and health sciences ,Prostate cancer ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Oncology ,Prostate ,030220 oncology & carcinogenesis ,medicine ,Cancer research ,Gene - Abstract
The androgen receptor (AR) signaling plays a key role in the development of the normal prostate as well as prostate cancer. While substantial efforts have been undertaken to study AR-regulated protein-coding genes in primary prostate cancer and castration-resistant prostate cancer, few studies have investigated the role of long noncoding RNAs. In this study, we employed transcriptome sequencing to delineate long noncoding RNAs (lncRNAs) associated with AR signaling in prostate cancer progression. ARlnc1 (AR-regulated lncRNA 1) was identified as being the top AR-induced, cancer-associated lncRNA in an integrative analysis of prostate cancer cell lines and tissues. Not only was ARlnc1 induced by AR, but ARlnc1 also was shown to sustain AR signaling by stabilizing the AR transcript via interaction with the AR 3' UTR. Knockdown of ARlnc1 suppressed AR expression, global AR signaling, and prostate cancer growth in vitro and in vivo. Taken together, these data support a role for ARlnc1 in maintaining a positive feedback loop that potentiates AR signaling during prostate cancer progression, and identifies ARlnc1 as a novel therapeutic target. Citation Format: Yajia Zhang, Sethuramasundaram Pitchiaya, Marcin Cieślik, Yashar S. Niknafs, Jean C. Tien, Yasuyuki Hosono, Lisha Wang, Yuanyuan Qiao, Xuhong Cao, Mats Ljungman, Hui Jiang, Rohit Mehra, Shuling Guo, Rohit Malik, Arul M. Chinnaiyan. The androgen receptor-regulated lncRNA landscape reveals a role for ARlnc1 in prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2458.
- Published
- 2018
37. Inactivation of CDK12 Delineates a Distinct Immunogenic Class of Advanced Prostate Cancer
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Yi-Mi Wu, Marcin Cieślik, Arul M. Chinnaiyan, Pankaj Vats, Navonil De Sarkar, Bruce Montgomery, Xuhong Cao, Elisabeth I. Heath, Weiping Zou, Johann S. de Bono, Robert J. Lonigro, Melissa A. Reimers, Felix Y. Feng, Jonathan Chou, Peter S. Nelson, Lisha Wang, Ajjai Alva, Dan R. Robinson, Yu Ning, and Lakshmi P. Kunju
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Male ,0301 basic medicine ,DNA Repair ,T-Lymphocytes ,Programmed Cell Death 1 Receptor ,Mutant ,Mutation, Missense ,Biology ,SPOP ,Genomic Instability ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Cell Line, Tumor ,medicine ,Humans ,RNA, Small Interfering ,Gene ,Neoplasm Staging ,Chemokine CCL21 ,Prostate ,Antibodies, Monoclonal ,Nuclear Proteins ,Prostatic Neoplasms ,Cell cycle ,medicine.disease ,Cyclin-Dependent Kinases ,Immune checkpoint ,Gene Expression Regulation, Neoplastic ,Repressor Proteins ,Phenotype ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer research ,RNA Interference ,Cancer biomarkers ,Tomography, X-Ray Computed ,Homologous recombination - Abstract
Using integrative genomic analysis of 360 metastatic castration-resistant prostate cancer (mCRPC) samples, we identified a novel subtype of prostate cancer typified by biallelic loss of CDK12 that is mutually exclusive with tumors driven by DNA repair deficiency, ETS fusions, and SPOP mutations. CDK12 loss is enriched in mCRPC relative to clinically localized disease and characterized by focal tandem duplications (FTDs) that lead to increased gene fusions and marked differential gene expression. FTDs associated with CDK12 loss result in highly recurrent gains at loci of genes involved in the cell cycle and DNA replication. CDK12 mutant cases are baseline diploid and do not exhibit DNA mutational signatures linked to defects in homologous recombination. CDK12 mutant cases are associated with elevated neoantigen burden ensuing from fusion-induced chimeric open reading frames and increased tumor T cell infiltration/clonal expansion. CDK12 inactivation thereby defines a distinct class of mCRPC that may benefit from immune checkpoint immunotherapy.
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- 2018
38. The role of entropy and polarity in intermolecular contacts in protein crystals
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Zygmunt S. Derewenda and Marcin Cieślik
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Models, Molecular ,Databases, Factual ,Protein Conformation ,Entropy ,Crystallography, X-Ray ,Crystal ,chemistry.chemical_compound ,Structural Biology ,Computer Simulation ,Amino Acids ,chemistry.chemical_classification ,Likelihood Functions ,Chemistry ,Intermolecular force ,Proteins ,General Medicine ,Contact order ,Research Papers ,Amino acid ,Crystallography ,Logistic Models ,Monomer ,Models, Chemical ,X-ray crystallography ,Crystallization ,Protein crystallization ,Hydrophobic and Hydrophilic Interactions ,Software ,Entropy (order and disorder) - Abstract
The integrity and X-ray diffraction quality of protein crystals depend on the three-dimensional order of relatively weak but reproducible intermolecular contacts. Despite their importance, relatively little attention has been paid to the chemical and physical nature of these contacts, which are often regarded as stochastic and thus not different from randomly selected protein surface patches. Here, logistic regression was used to analyze crystal contacts in a database of 821 unambiguously monomeric proteins with structures determined to 2.5 A resolution or better. It is shown that the propensity of a surface residue for incorporation into a crystal contact is not a linear function of its solvent-accessible surface area and that amino acids with low exposed surfaces, which are typically small and hydrophobic, have been underestimated with respect to their contact-forming potential by earlier area-based calculations. For any given solvent-exposed surface, small and hydrophobic residues are more likely to be involved in crystal contacts than large and charged amino acids. Side-chain entropy is the single physicochemical property that is most negatively correlated with the involvement of amino acids in crystal contacts. It is also shown that crystal contacts with larger buried surfaces containing eight or more amino acids have cores that are depleted of polar amino acids.
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- 2009
39. Abstractions, Algorithms and Data Structures for Structural Bioinformatics in PyCogent
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Cameron Mura, Zygmunt S. Derewenda, and Marcin Cieślik
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FOS: Computer and information sciences ,Computer science ,Extensibility ,General Biochemistry, Genetics and Molecular Biology ,Computer Programs ,Computer Science - Software Engineering ,03 medical and health sciences ,Structural bioinformatics ,Computer Science - Data Structures and Algorithms ,Leverage (statistics) ,Data Structures and Algorithms (cs.DS) ,Implementation ,030304 developmental biology ,computer.programming_language ,0303 health sciences ,030302 biochemistry & molecular biology ,Protein structure analysis ,Biomolecules (q-bio.BM) ,Python (programming language) ,File format ,Data structure ,Software Engineering (cs.SE) ,ComputingMethodologies_PATTERNRECOGNITION ,Quantitative Biology - Biomolecules ,FOS: Biological sciences ,Algorithm ,computer - Abstract
To facilitate flexible and efficient structural bioinformatics analyses, new functionality for three-dimensional structure processing and analysis has been introduced into PyCogent -- a popular feature-rich framework for sequence-based bioinformatics, but one which has lacked equally powerful tools for handling stuctural/coordinate-based data. Extensible Python modules have been developed, which provide object-oriented abstractions (based on a hierarchical representation of macromolecules), efficient data structures (e.g. kD-trees), fast implementations of common algorithms (e.g. surface-area calculations), read/write support for Protein Data Bank-related file formats and wrappers for external command-line applications (e.g. Stride). Integration of this code into PyCogent is symbiotic, allowing sequence-based work to benefit from structure-derived data and, reciprocally, enabling structural studies to leverage PyCogent's versatile tools for phylogenetic and evolutionary analyses., Comment: 36 pages, 4 figures (including supplemental information)
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- 2014
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40. Epigenetic reprogramming in the epithelial-to-mesenchymal transition
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Stefan Bekiranov, Lisa G. Gray, Natalya Baranova, Marcin Cieślik, Stephen A. Hoang, Sanjay Chodaparambil, David F. Allison, Jake Wamsley, Manish Kumar, and Marty W. Mayo
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Genetics ,Microarray analysis techniques ,lcsh:R ,lcsh:Medicine ,General Medicine ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Chromatin ,Cell biology ,Epigenetic Profile ,Oral Presentation ,lcsh:Q ,Epithelial–mesenchymal transition ,Epigenetics ,lcsh:Science ,Enhancer ,Reprogramming ,Transcription factor - Abstract
The epithelial-to-mesenchymal transition (EMT) is a cellular dedifferentiation process that is critical to development, wound healing and metastasis. Like other cell state transitions, such as differentiation, EMT is accompanied by genome-wide epigenetic reprogramming. However, the relationship between reprogramming and functional changes in the cell is poorly understood. In an A549 non-small cell lung cancer EMT model system we observed changes in chromatin state between epithelial and mesenchymal states. Multivariate analyses were applied to paired (epithelial and mesenchymal) ChIP-seq data for 18 histone modifications/variants and expression microarray data. We observed epigenetic co-regulation of genes associated with EMT, as well as their proximal enhancers. We also observed epigenetic activation or repression of functionally distinct sets of enhancers. These genes and enhancers are regulated and bound by a small set of transcription factors, specifically AP-1, NF-κB and c-Myc. These transcription factors themselves also a show an epigenetic profile similar to the EMT-related genes. Together, these observations suggest a chromatin-mediated transcriptional feedback mechanism that establishes and maintains the phenotypic switch.
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- 2012
41. Direct cellular reprogramming enables development of viral T antigen–driven Merkel cell carcinoma in mice
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Monique E. Verhaegen, Paul W. Harms, Julia J. Van Goor, Jacob Arche, Matthew T. Patrick, Dawn Wilbert, Haley Zabawa, Marina Grachtchouk, Chia-Jen Liu, Kevin Hu, Michael C. Kelly, Ping Chen, Thomas L. Saunders, Stephan Weidinger, Li-Jyun Syu, John S. Runge, Johann E. Gudjonsson, Sunny Y. Wong, Isaac Brownell, Marcin Cieslik, Aaron M. Udager, Arul M. Chinnaiyan, Lam C. Tsoi, and Andrzej A. Dlugosz
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Dermatology ,Oncology ,Medicine - Abstract
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer that frequently carries an integrated Merkel cell polyomavirus (MCPyV) genome and expresses viral transforming antigens (TAgs). MCC tumor cells also express signature genes detected in skin-resident, postmitotic Merkel cells, including atonal bHLH transcription factor 1 (ATOH1), which is required for Merkel cell development from epidermal progenitors. We now report the use of in vivo cellular reprogramming, using ATOH1, to drive MCC development from murine epidermis. We generated mice that conditionally expressed MCPyV TAgs and ATOH1 in epidermal cells, yielding microscopic collections of proliferating MCC-like cells arising from hair follicles. Immunostaining of these nascent tumors revealed p53 accumulation and apoptosis, and targeted deletion of transformation related protein 53 (Trp53) led to development of gross skin tumors with classic MCC histology and marker expression. Global transcriptome analysis confirmed the close similarity of mouse and human MCCs, and hierarchical clustering showed conserved upregulation of signature genes. Our data establish that expression of MCPyV TAgs in ATOH1-reprogrammed epidermal cells and their neuroendocrine progeny initiates hair follicle–derived MCC tumorigenesis in adult mice. Moreover, progression to full-blown MCC in this model requires loss of p53, mimicking the functional inhibition of p53 reported in human MCPyV-positive MCCs.
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- 2022
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42. Metabolism drives macrophage heterogeneity in the tumor microenvironment
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Shasha Li, Jiali Yu, Amanda Huber, Ilona Kryczek, Zhuwen Wang, Long Jiang, Xiong Li, Wan Du, Gaopeng Li, Shuang Wei, Linda Vatan, Wojciech Szeliga, Arul M. Chinnaiyan, Michael D. Green, Marcin Cieslik, and Weiping Zou
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CP: Cancer ,CP: Metabolism ,Biology (General) ,QH301-705.5 - Abstract
Summary: Tumor-associated macrophages (TAMs) are a major cellular component in the tumor microenvironment (TME). However, the relationship between the phenotype and metabolic pattern of TAMs remains poorly understood. We performed single-cell transcriptome profiling on hepatic TAMs from mice bearing liver metastatic tumors. We find that TAMs manifest high heterogeneity at the levels of transcription, development, metabolism, and function. Integrative analyses and validation experiments indicate that increased purine metabolism is a feature of TAMs with pro-tumor and terminal differentiation phenotypes. Like mouse TAMs, human TAMs are highly heterogeneous. Human TAMs with increased purine metabolism exhibit a pro-tumor phenotype and correlate with poor therapeutic efficacy to immune checkpoint blockade. Altogether, our work demonstrates that TAMs are developmentally, metabolically, and functionally heterogeneous and purine metabolism may be a key metabolic feature of a pro-tumor macrophage population.
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- 2022
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43. Abstract 3636: Targeting the MLL complex in castration resistant prostate cancer
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Felix Y. Feng, Xuhong Cao, John R. Prensner, Xiaoju Wang, Arul M. Chinnaiyan, Xia Jiang, June Escara-Wilke, Dmitry Borkin, Rohit Malik, Irfan A. Asangani, Amjad Khan, Jolanta Grembecka, Tomasz Cierpicki, Matthew K. Iyer, Marcin Cieślik, Yi-Mi Wu, and Rachell Stender
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Oncology ,Cancer Research ,medicine.medical_specialty ,Prostate cancer ,business.industry ,Internal medicine ,medicine ,Castration resistant ,medicine.disease ,business - Abstract
Resistance to androgen deprivation therapies and increased androgen receptor (AR) activity are major drivers of castration resistant prostate cancer (CRPC). Substantial prior work has focused on targeting AR directly; however, the identification and therapeutic targeting of co-activators of AR signaling remains an underexplored area of potential clinical significance. Here we demonstrate that the MLL (mixed-lineage leukemia) complex, a well-known contributor in MLL-fusion-positive leukemia, acts as a co-activator of AR signaling. AR directly interacts with the MLL complex via its critical subunit, menin. Small molecule inhibition of the menin-MLL interaction blocks AR signaling and inhibits the growth of castration resistant tumors in vivo. Furthermore, we find that menin is up-regulated in castration resistant prostate cancer and high expression correlates with poor overall survival. Taken together, our study identifies the MLL complex as a critical co-activator of AR that can be targeted in advanced prostate cancer. Citation Format: Rohit Malik, Amjad P. Khan, Irfan A. Asangani, Marcin Cieślik, John R. Prensner, Xiaoju Wang, Matthew K. Iyer, Xia Jiang, Dmitry Borkin, June Escara-Wilke, Rachell Stender, Yi-Mi Wu, Xuhong Cao, Felix Y. Feng, Jolanta Grembecka, Tomasz Cierpicki, Arul M. Chinnaiyan. Targeting the MLL complex in castration resistant prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3636. doi:10.1158/1538-7445.AM2015-3636
- Published
- 2015
44. Combinatorial epigenetic patterns as quantitative predictors of chromatin biology
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Marcin Cieślik and Stefan Bekiranov
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Epigenomics ,Chromatin Immunoprecipitation ,Computational biology ,Biology ,Genome ,Deep sequencing ,Non-negative matrix factorization ,Histones ,User-Computer Interface ,Genetics ,Humans ,Epigenetics ,Promoter Regions, Genetic ,Embryonic Stem Cells ,Internet ,Principal Component Analysis ,Dimensionality reduction ,Methodology Article ,Chromatin ,ROC Curve ,Area Under Curve ,DNA microarray ,Chromatin immunoprecipitation ,Algorithms ,Biotechnology ,Protein Binding - Abstract
Chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) is the most widely used method for characterizing the epigenetic states of chromatin on a genomic scale. With the recent availability of large genome-wide data sets, often comprising several epigenetic marks, novel approaches are required to explore functionally relevant interactions between histone modifications. Computational discovery of "chromatin states" defined by such combinatorial interactions enabled descriptive annotations of genomes, but more quantitative approaches are needed to progress towards predictive models. We propose non-negative matrix factorization (NMF) as a new unsupervised method to discover combinatorial patterns of epigenetic marks that frequently co-occur in subsets of genomic regions. We show that this small set of combinatorial "codes" can be effectively displayed and interpreted. NMF codes enable dimensionality reduction and have desirable statistical properties for regression and classification tasks. We demonstrate the utility of codes in the quantitative prediction of Pol2-binding and the discrimination between Pol2-bound promoters and enhancers. Finally, we show that specific codes can be linked to molecular pathways and targets of pluripotency genes during differentiation. We have introduced and evaluated a new computational approach to represent combinatorial patterns of epigenetic marks as quantitative variables suitable for predictive modeling and supervised machine learning. To foster widespread adoption of this method we make it available as an open-source software-package – epicode at https://github.com/mcieslik-mctp/epicode .
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- 2014
45. A lightweight, flow-based toolkit for parallel and distributed bioinformatics pipelines
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Cameron Mura and Marcin Cieślik
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Workstation ,Computer science ,Distributed computing ,Bioinformatics ,computer.software_genre ,lcsh:Computer applications to medicine. Medical informatics ,Extensibility ,Biochemistry ,Computing Methodologies ,law.invention ,Workflow ,Software ,Structural Biology ,law ,Software system ,lcsh:QH301-705.5 ,Molecular Biology ,computer.programming_language ,business.industry ,Applied Mathematics ,Dataflow programming ,Computational Biology ,Python (programming language) ,Modular design ,Directed acyclic graph ,Computer Science Applications ,Grid computing ,lcsh:Biology (General) ,Software deployment ,lcsh:R858-859.7 ,Programming Languages ,business ,computer - Abstract
Background Bioinformatic analyses typically proceed as chains of data-processing tasks. A pipeline, or 'workflow', is a well-defined protocol, with a specific structure defined by the topology of data-flow interdependencies, and a particular functionality arising from the data transformations applied at each step. In computer science, the dataflow programming (DFP) paradigm defines software systems constructed in this manner, as networks of message-passing components. Thus, bioinformatic workflows can be naturally mapped onto DFP concepts. Results To enable the flexible creation and execution of bioinformatics dataflows, we have written a modular framework for parallel pipelines in Python ('PaPy'). A PaPy workflow is created from re-usable components connected by data-pipes into a directed acyclic graph, which together define nested higher-order map functions. The successive functional transformations of input data are evaluated on flexibly pooled compute resources, either local or remote. Input items are processed in batches of adjustable size, all flowing one to tune the trade-off between parallelism and lazy-evaluation (memory consumption). An add-on module ('NuBio') facilitates the creation of bioinformatics workflows by providing domain specific data-containers (e.g., for biomolecular sequences, alignments, structures) and functionality (e.g., to parse/write standard file formats). Conclusions PaPy offers a modular framework for the creation and deployment of parallel and distributed data-processing workflows. Pipelines derive their functionality from user-written, data-coupled components, so PaPy also can be viewed as a lightweight toolkit for extensible, flow-based bioinformatics data-processing. The simplicity and flexibility of distributed PaPy pipelines may help users bridge the gap between traditional desktop/workstation and grid computing. PaPy is freely distributed as open-source Python code at http://muralab.org/PaPy, and includes extensive documentation and annotated usage examples.
- Published
- 2011
46. PFA ependymoma-associated protein EZHIP inhibits PRC2 activity through a H3 K27M-like mechanism
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Siddhant U. Jain, Truman J. Do, Peder J. Lund, Andrew Q. Rashoff, Katharine L. Diehl, Marcin Cieslik, Andrea Bajic, Nikoleta Juretic, Shriya Deshmukh, Sriram Venneti, Tom W. Muir, Benjamin A. Garcia, Nada Jabado, and Peter W. Lewis
- Subjects
Science - Abstract
PFA tumours express high levels of EZHIP (also known as CXORF67). Here the authors find that EZHIP directly interacts with the active site of EZH2 and is a competitive inhibitor of PRC2 and that EZHIP gives rise to H3K27me3 genomic profile similar to the K27M oncohistone.
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- 2019
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47. Epigenetic coordination of signaling pathways during the epithelial-mesenchymal transition
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Marty W. Mayo, Sanjay Chodaparambil, David R. Jones, Xiaojiang Xu, J. Jacob Wamsley, Stefan Bekiranov, Manish Kumar, David F. Allison, Lisa G. Gray, Marcin Cieślik, Stephen A. Hoang, and Natalya Baranova
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Cell signaling ,Biology ,Bioinformatics ,Chromatin remodeling ,Feedback ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Genetics ,Epithelial–mesenchymal transition ,Epigenetics ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,Research ,EMT ,Cancer ,Reprogramming ,medicine.disease ,Chromatin ,3. Good health ,030220 oncology & carcinogenesis ,Cancer research ,Signal transduction - Abstract
Background The epithelial-mesenchymal transition (EMT) is a de-differentiation process required for wound healing and development. In tumors of epithelial origin aberrant induction of EMT contributes to cancer progression and metastasis. Studies have begun to implicate epigenetic reprogramming in EMT; however, the relationship between reprogramming and the coordination of cellular processes is largely unexplored. We have previously developed a system to study EMT in a canonical non-small cell lung cancer (NSCLC) model. In this system we have shown that the induction of EMT results in constitutive NF-κB activity. We hypothesized a role for chromatin remodeling in the sustained deregulation of cellular signaling pathways. Results We mapped sixteen histone modifications and two variants for epithelial and mesenchymal states. Combinatorial patterns of epigenetic changes were quantified at gene and enhancer loci. We found a distinct chromatin signature among genes in well-established EMT pathways. Strikingly, these genes are only a small minority of those that are differentially expressed. At putative enhancers of genes with the ‘EMT-signature’ we observed highly coordinated epigenetic activation or repression. Furthermore, enhancers that are activated are bound by a set of transcription factors that is distinct from those that bind repressed enhancers. Upregulated genes with the ‘EMT-signature’ are upstream regulators of NF-κB, but are also bound by NF-κB at their promoters and enhancers. These results suggest a chromatin-mediated positive feedback as a likely mechanism for sustained NF-κB activation. Conclusions There is highly specific epigenetic regulation at genes and enhancers across several pathways critical to EMT. The sites of these changes in chromatin state implicate several inducible transcription factors with critical roles in EMT (NF-κB, AP-1 and MYC) as targets of this reprogramming. Furthermore, we find evidence that suggests that these transcription factors are in chromatin-mediated transcriptional feedback loops that regulate critical EMT genes. In sum, we establish an important link between chromatin remodeling and shifts in cellular reprogramming.
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