44 results on '"Park, Kwon-Sik"'
Search Results
2. Effect of chromatin modifiers on the plasticity and immunogenicity of small-cell lung cancer
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Kirk, Nicole A., Kim, Kee-Beom, and Park, Kwon-Sik
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- 2022
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3. Regulation of UHRF1 acetylation by TIP60 is important for colon cancer cell proliferation
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Hong, Ye Joo, Park, Junyoung, Hahm, Ja Young, Kim, Song Hyun, Lee, Dong Ho, Park, Kwon-Sik, and Seo, Sang-Beom
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- 2022
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4. Opa1 and Drp1 reciprocally regulate cristae morphology, ETC function, and NAD+ regeneration in KRas-mutant lung adenocarcinoma
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Sessions, Dane T., Kim, Kee-Beom, Kashatus, Jennifer A., Churchill, Nikolas, Park, Kwon-Sik, Mayo, Marty W., Sesaki, Hiromi, and Kashatus, David F.
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- 2022
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5. New Approaches to SCLC Therapy: From the Laboratory to the Clinic
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Poirier, John T., George, Julie, Owonikoko, Taofeek K., Berns, Anton, Brambilla, Elisabeth, Byers, Lauren A., Carbone, David, Chen, Huanhuan J., Christensen, Camilla L., Dive, Caroline, Farago, Anna F., Govindan, Ramaswamy, Hann, Christine, Hellmann, Matthew D., Horn, Leora, Johnson, Jane E., Ju, Young S., Kang, Sumin, Krasnow, Mark, Lee, James, Lee, Se-Hoon, Lehman, Jonathan, Lok, Benjamin, Lovly, Christine, MacPherson, David, McFadden, David, Minna, John, Oser, Matthew, Park, Keunchil, Park, Kwon-Sik, Pommier, Yves, Quaranta, Vito, Ready, Neal, Sage, Julien, Scagliotti, Giorgio, Sos, Martin L., Sutherland, Kate D., Travis, William D., Vakoc, Christopher R., Wait, Sarah J., Wistuba, Ignacio, Wong, Kwok Kin, Zhang, Hua, Daigneault, Jillian, Wiens, Jacinta, Rudin, Charles M., and Oliver, Trudy G.
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- 2020
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6. Reprogramming fatty acyl specificity of lipid kinases via C1 domain engineering
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Ware, Timothy B., Franks, Caroline E., Granade, Mitchell E., Zhang, Mingxing, Kim, Kee-Beom, Park, Kwon-Sik, Gahlmann, Andreas, Harris, Thurl E., and Hsu, Ku-Lung
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- 2020
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7. Recent progress in mapping the emerging landscape of the small-cell lung cancer genome
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Kim, Kee-Beom, Dunn, Colin T., and Park, Kwon-Sik
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- 2019
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8. CRACD loss induces neuroendocrine cell plasticity of lung adenocarcinoma
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Kim, Bongjun, Zhang, Shengzhe, Huang, Yuanjian, Ko, Kyung-Pil, Jung, Youn-Sang, Jang, Jinho, Zou, Gengyi, Zhang, Jie, Jun, Sohee, Kim, Kee-Beom, Park, Kwon-Sik, and Park, Jae-Il
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- 2024
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9. Phase I Study of Entinostat, Atezolizumab, Carboplatin, and Etoposide in Previously Untreated Extensive-Stage Small Cell Lung Cancer, ETCTN 10399.
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Gentzler, Ryan D, Villaruz, Liza C, Rhee, John C, Horton, Bethany, Mock, Joseph, Hanley, Michael, Kim, Kyeongmin, Rudek, Michelle A, Phelps, Mitch A, Carducci, Michael A, Piekarz, Richard, Park, Kwon-Sik, Bullock, Timothy N, and Rudin, Charles M
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LUNG cancer ,ETOPOSIDE ,BIOLOGICAL models ,CARBOPLATIN ,CLINICAL trials ,LUNG tumors ,ANTINEOPLASTIC agents ,MONOCLONAL antibodies ,NEUTROPENIA ,DESCRIPTIVE statistics ,THROMBOCYTOPENIA ,ADVERSE health care events ,PATIENT safety - Abstract
Background: CREBBP and EP300 mutations occur at a frequency of 15% and 13%, respectively, in small cell lung cancer (SCLC), and preclinical models demonstrated susceptibility to targeting with HDAC inhibitors. Methods: Patients with treatment-naïve extensive-stage SCLC, ECOG ≤2 were enrolled and treated with entinostat orally weekly (4 dose levels, DL) in combination with standard dose carboplatin, etoposide, and atezolizumab. Cohort allocation was determined by Bayesian optimal interval (BOIN) design targeting an MTD with a DLT rate of 20%. Results: Three patients were enrolled and treated at DL1 with entinostat 2 mg. Patients were aged 69-83; 2 male, 1 female; 2 were ECOG 1, and 1 was ECOG 0. The most common adverse events (AEs) were anemia (3), neutropenia (3), thrombocytopenia (2), leukopenia (2), and hypocalcemia (2). Two experienced DLTs during cycle 1: (1) grade (Gr) 4 febrile neutropenia, and (1) Gr 5 sepsis. BOIN design required stopping accrual to DL1, and the trial was closed to further accrual. Entinostat and atezolizumab pharmacokinetics were both comparable to historical controls. Conclusion: Addition of entinostat to atezolizumab, carboplatin, and etoposide is unsafe and resulted in early onset and severe neutropenia, thrombocytopenia. Further exploration of entinostat with carboplatin, etoposide, and atezolizumab should not be explored. (ClinicalTrials.gov Identifier: NCT04631029). This phase I trial evaluated the safety of combining an HDAC inhibitor, entinostat, with standard of care chemotherapy and immunotherapy for small cell lung cancer. [ABSTRACT FROM AUTHOR]
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- 2023
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10. CRACD, a gatekeeper restricting proliferation, heterogeneity, and immune evasion of small cell lung cancer
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Zhang, Shengzhe, Kim, Kee-Beom, Huang, Yuanjian, Kim, Dong-Wook, Kim, Bongjun, Ko, Kyung-Pil, Zou, Gengyi, Zhang, Jie, Jun, Sohee, Kirk, Nicole A., Hwang, Ye Eun, Ban, Young Ho, Chan, Joseph M., Rudin, Charles M., Park, Kwon-Sik, and Park, Jae-Il
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Article - Abstract
Small cell lung carcinoma (SCLC) is a lethal neuroendocrine type of lung cancer with limited therapeutic options. Despite recent advances in cancer immunotherapy, the efficacy of immunotherapy is limited to a subset of patients with SCLC. However, the mechanisms responsible for refractoriness to immunotherapy remain elusive. CRACD (capping protein inhibiting regulator of actin dynamics; KIAA1211/CRAD) is frequently mutated and transcriptionally downregulated in SCLC. Here we show that Cracd knockout (KO) enhances transformation of preneoplastic neuroendocrine cells and significantly accelerates SCLC development initiated by loss of Rb1, Trp53, and Rbl2 in the lung epithelium of mice. Cracd KO increases tumor cell heterogeneity in SCLC tumors. Notably, the Cracd-deficient SCLC tumors display exclusion of CD8(+) T cells, which coincides with epigenetic suppression of the MHC-I pathway. Single-cell transcriptomic analysis identifies SCLC patient tumors with concomitant inactivation of CRACD and impairment of tumor antigen presentation. These findings define CRACD as a novel tumor suppressor that regulates the proliferation and immune recognition of SCLC cells, providing new insight into the mechanisms by which SCLC evades immune surveillance.
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- 2023
11. In situ 10-cell RNA sequencing in tissue and tumor biopsy samples
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Singh, Shambhavi, Wang, Lixin, Schaff, Dylan L., Sutcliffe, Matthew D., Koeppel, Alex F., Kim, Jungeun, Onengut-Gumuscu, Suna, Park, Kwon-Sik, Zong, Hui, and Janes, Kevin A.
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- 2019
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12. Comprehensive genomic profiles of small cell lung cancer
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George, Julie, Lim, Jing Shan, Jang, Se Jin, Cun, Yupeng, Ozretić, Luka, Kong, Gu, Leenders, Frauke, Lu, Xin, Fernández-Cuesta, Lynnette, Bosco, Graziella, Müller, Christian, Dahmen, Ilona, Jahchan, Nadine S., Park, Kwon-Sik, Yang, Dian, Karnezis, Anthony N., Vaka, Dedeepya, Torres, Angela, Wang, Maia Segura, Korbel, Jan O., Menon, Roopika, Chun, Sung-Min, Kim, Deokhoon, Wilkerson, Matt, Hayes, Neil, Engelmann, David, Pützer, Brigitte, Bos, Marc, Michels, Sebastian, Vlasic, Ignacija, Seidel, Danila, Pinther, Berit, Schaub, Philipp, Becker, Christian, Altmüller, Janine, Yokota, Jun, Kohno, Takashi, Iwakawa, Reika, Tsuta, Koji, Noguchi, Masayuki, Muley, Thomas, Hoffmann, Hans, Schnabel, Philipp A., Petersen, Iver, Chen, Yuan, Soltermann, Alex, Tischler, Verena, Choi, Chang-min, Kim, Yong-Hee, Massion, Pierre P., Zou, Yong, Jovanovic, Dragana, Kontic, Milica, Wright, Gavin M., Russell, Prudence A., Solomon, Benjamin, Koch, Ina, Lindner, Michael, Muscarella, Lucia A., la Torre, Annamaria, Field, John K., Jakopovic, Marko, Knezevic, Jelena, Castaños-Vélez, Esmeralda, Roz, Luca, Pastorino, Ugo, Brustugun, Odd-Terje, Lund-Iversen, Marius, Thunnissen, Erik, Köhler, Jens, Schuler, Martin, Botling, Johan, Sandelin, Martin, Sanchez-Cespedes, Montserrat, Salvesen, Helga B., Achter, Viktor, Lang, Ulrich, Bogus, Magdalena, Schneider, Peter M., Zander, Thomas, Ansén, Sascha, Hallek, Michael, Wolf, Jürgen, Vingron, Martin, Yatabe, Yasushi, Travis, William D., Nürnberg, Peter, Reinhardt, Christian, Perner, Sven, Heukamp, Lukas, Büttner, Reinhard, Haas, Stefan A., Brambilla, Elisabeth, Peifer, Martin, Sage, Julien, and Thomas, Roman K.
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- 2015
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13. Lung Cancer Signatures in Plasma Based on Proteome Profiling of Mouse Tumor Models
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Taguchi, Ayumu, Politi, Katerina, Pitteri, Sharon J., Lockwood, William W., Faça, Vitor M., Kelly-Spratt, Karen, Wong, Chee-Hong, Zhang, Qing, Chin, Alice, Park, Kwon-Sik, Goodman, Gary, Gazdar, Adi F., Sage, Julien, Dinulescu, Daniela M., Kucherlapati, Raju, DePinho, Ronald A., Kemp, Christopher J., Varmus, Harold E., and Hanash, Samir M.
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- 2011
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14. Validation of L-Myc as a viable therapeutic target in small cell lung cancer
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Kim, Dong-Wook, Dunn, Colin Thomas, Sage, Julien, and Park, Kwon-Sik
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- 2016
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15. A crucial requirement for Hedgehog signaling in small cell lung cancer
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Park, Kwon-Sik, Martelotto, Luciano G., Peifer, Martin, Sos, Martin L., Karnezis, Anthony N., Mahjoub, Moe R., Bernard, Katie, Conklin, Jamie F., Szczepny, Anette, Yuan, Jing, Guo, Ribo, Ospina, Beatrice, Falzon, Jeanette, Bennett, Samara, Brown, Tracey J., Markovic, Ana, Devereux, Wendy L., Ocasio, Cory A., Chen, James K., Stearns, Tim, Thomas, Roman K., Dorsch, Marion, Buonamici, Silvia, Watkins, D.Neil, Peacock, Craig D., and Sage, Julien
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Hedgehog proteins -- Physiological aspects -- Genetic aspects -- Research ,Lung cancer, Non-small cell -- Development and progression -- Genetic aspects -- Care and treatment -- Research ,Cellular signal transduction -- Physiological aspects -- Genetic aspects -- Research ,Biological sciences ,Health - Abstract
Small-cell lung cancer (SCLC) is an aggressive neuroendocrine subtype of lung cancer for which there is no effective treatment (1,2). Using a mouse model in which deletion of Rbl and Trp53 in the lung epithelium of adult mice induces SCLC (3,4), we found that the Hedgehog signaling pathway is activated in SCLC cells independently of the lung microenvironment. Constitutive activation of the Hedgehog signaling molecule Smoothened (Smo) promoted the clonogenicity of human SCLC in vitro and the initiation and progression of mouse SCLC in vivo. Reciprocally, deletion of Smo in Rbl and Trp53-mutant lung epithelial cells strongly suppressed SCLC initiation and progression in mice. Furthermore, pharmacological blockade of Hedgehog signaling inhibited the growth of mouse and human SCLC, most notably following chemotherapy. These findings show a crucial cell-intrinsic role for Hedgehog signaling in the development and maintenance of SCLC and identify Hedgehog pathway inhibition as a therapeutic strategy to slow the progression of disease and delay cancer recurrence in individuals with SCLC., Activation of Hedgehog signaling has been reported in a subset of human SCLC cell lines and tumors (5-8) without changes in Hedgehog pathway gene copy numbers (9). Furthermore, we sequenced [...]
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- 2011
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16. New approaches to small cell lung cancer therapy : from the laboratory to the clinic
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Poirier, John T., George, Julie, Owonikoko, Taofeek K., Berns, Anton, Brambilla, Elisabeth, Byers, Lauren Averett, Carbone, David, Chen, Huanhuan Joyce, Christensen, Camilla L., Dive, Caroline, Farago, Anna F., Govindan, Ramaswamy, Hann, Christine, Hellmann, Matthew D., Horn, Leora, Johnson, Jane E., Ju, Young Seok, Kang, Sumin, Krasnow, Mark, Lee, James, Lee, Se-Hoon, Lehman, Jonathan, Lok, Benjamin, Lovly, Christine, MacPherson, David, McFadden, David, Minna, John, Oser, Matthew, Park, Keunchil, Park, Kwon-Sik, Pommier, Yves, Quaranta, Vito, Ready, Neal, Sage, Julien, Scagliotti, Giorgio, Sos, Martin L., Sutherland, Kate D., Travis, William D., Vakoc, Christopher R., Wait, Sarah J., Wistuba, Ignacio, Wong, Kwok Kin, Zhang, Hua, Daigneault, Jillian, Wiens, Jacinta, Rudin, Charles M., and Oliver, Trudy G.
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Lung Neoplasms ,Humans ,Neoplasm Recurrence, Local ,Precision Medicine ,Laboratories ,Small Cell Lung Carcinoma ,Article - Abstract
Small cell lung cancer patient outcomes have not yet been significantly impacted by the revolution in precision oncology, primarily due to a paucity of genetic alterations in actionable driver oncogenes. Nevertheless, systemic therapies that include immunotherapy are beginning to show promise in the clinic. While these results are encouraging, many patients do not respond to or rapidly recur after current regimens, necessitating alternative or complementary therapeutic strategies. In this review, we discuss ongoing investigations into the pathobiology of this recalcitrant cancer and the therapeutic vulnerabilities that are exposed by the disease state. Included within this discussion is a snapshot of the current biomarker and clinical trial landscapes for small cell lung cancer. Finally, we identify key knowledge gaps that should be addressed in order to advance the field in pursuit of reduced small cell lung cancer mortality. This review largely summarizes work presented at the Third Biennial IASLC Small Cell Lung Cancer Meeting.
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- 2020
17. SPDEF regulates goblet cell hyperplasia in the airway epithelium
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Park, Kwon-Sik, Korfhagen, Thomas R., Bruno, Michael D., Kitzmiller, Joseph A., Wan, Huajing, Wert, Susan E., Hershey, Gurjit K. Khurana, Chen, Gang, and Whitsett, Jeffrey A.
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Gene expression -- Research ,Hyperplasia -- Research ,Trachea -- Research - Abstract
Goblet cell hyperplasia and mucous hypersecretion contribute to the pathogenesis of chronic pulmonary diseases including cystic fibrosis, asthma, and chronic obstructive pulmonary disease. In the present work, mouse SAM pointed [...]
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- 2007
18. Oncogenic role of FGFR1 and vulnerability of RBL2-FGFR1 axis in small cell lung cancer development
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Kim, Kee-Beom, Kim, Youngchul, Kim, Dong-Wook, and Park, Kwon-Sik
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stomatognathic diseases - Abstract
The observation of recurrent fibroblast growth factor receptor 1 (FGFR1) amplification in small cell lung cancer (SCLC) raised the possibility of targeting the FGFR1 pathway to treat this aggressive disease. However, in vivo evidence for the significance of FGFR1 in SCLC development is lacking, and previous studies indicate a need for additional biomarkers to stratify patient tumours for anti-FGFR1 therapeutics. Here, we found that ectopic Fgfr1 expression in precancerous neuroendocrine cells (preSCs) increased cell growth in vitro and tumour formation in immune-compromised mice, results that coincided with transcriptomic changes indicative of altered differentiation and enhanced proliferation. Interestingly, Fgfr1 deletion suppressed tumour development in Rb1/Trp53/Rbl2 -mutant mice but not in Rb1/Trp53 -mutant mice. This Rbl2-dependent difference in phenotype suggests a functional link between this well-known tumour suppressor and FGFR1 signalling during SCLC development. Rbl2 knockout in preSCs selectively increased Fgfr1 expression while promoting tumour formation. Rbl2 loss also correlated with Fgfr1 induction in allograft tumours generated from preSCs carrying oncogenic mutations and primary tumours developed in the Rb1/Trp53 -mutant mouse model. These results demonstrate the importance of enhanced FGFR1 and the vulnerability of the RBL2-FGFR1 axis for SCLC development.
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- 2019
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19. Sox17 influences the differentiation of respiratory epithelial cells
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Park, Kwon-Sik, Wells, James M., Zorn, Aaron M., Wert, Susan E., and Whitsett, Jeffrey A.
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Biological sciences - Abstract
To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2006.02.038 Byline: Kwon-Sik Park (a), James M. Wells (b), Aaron M. Zorn (b), Susan E. Wert (a), Jeffrey A. Whitsett (a) Keywords: Transcription factor; Sox17; Foxj1; Progenitor cells; Lung; Transdifferentiation Abstract: The Sry-related HMG box transcription factor, Sox17, is required for formation of definitive endoderm that gives rise to various organs, including thyroid, lung, liver, pancreas, and intestine. While expressed at high levels in the embryonic endoderm, Sox17 is also expressed in mature tissues, including the lung. Sox17 expression in respiratory epithelial cells was first detected in the fetal lung at embryonic day 18. Thereafter, Sox17 expression was restricted primarily to ciliated cells, suggesting its potential role in airway cell differentiation. When expressed in epithelial cells of the embryonic lung, Sox17 inhibited peripheral epithelial cell differentiation and disrupted branching morphogenesis. In vitro, Sox17 inhibited Sftpc and enhanced Foxj1 promoter activity, consistent with its expression in proximal airway cells. Conditional expression of Sox17 in peripheral respiratory epithelial cells of adult lung induced hyperplastic clusters of cells expressing increased levels of [beta]-catenin and differentiation markers representing multiple proximal respiratory epithelial cell types. Sox17 prolonged survival and enhanced growth and differentiation of respiratory epithelial cells in vitro. Sox17 induced plasticity of respiratory epithelial cells, reprogramming alveolar cells into epithelial cells with characteristics more typical of the proximal airway. Sites of expression and the effects of Sox17 in vivo and in vitro are consistent with a role for Sox17 or other members of the Sox family of transcription factors in differentiation of the conducting airway epithelium. Author Affiliation: (a) Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45229-3039, USA (b) Division of Developmental Biology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45229-3039, USA Article History: Received 31 October 2005; Revised 20 February 2006; Accepted 22 February 2006
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- 2006
20. Transdifferentiation of Ciliated Cells during Repair of the Respiratory Epithelium
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Park, Kwon-Sik, Wells, James M., Zorn, Aaron M., Wert, Susan E., Laubach, Victor E., Fernandez, Lucas G., and Whitsett, Jeffrey A.
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- 2006
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21. BCAT1 affects mitochondrial metabolism independently of leucine transamination in activated human macrophages.
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Jeong-Hun Ko, Olona, Antoni, Papathanassiu, Adonia E., Buang, Norzawani, Park, Kwon-Sik, Costa, Ana S. H., Mauro, Claudio, Frezza, Christian, and Behmoaras, Jacques
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LEUCINE ,MACROPHAGES ,MACROPHAGE activation ,METABOLISM ,MITOCHONDRIA ,TRICARBOXYLIC acids - Abstract
In response to environmental stimuli, macrophages change their nutrient consumption and undergo an early metabolic adaptation that progressively shapes their polarization state. During the transient, early phase of pro-inflammatory macrophage activation, an increase in tricarboxylic acid (TCA) cycle activity has been reported, but the relative contribution of branched-chain amino acid (BCAA) leucine remains to be determined. Here, we show that glucose but not glutamine is a major contributor of the increase in TCA cycle metabolites during early macrophage activation in humans.We then show that, although uptake of BCAAs is not altered, their transamination by BCAT1 is increased following 8 h lipopolysaccharide (LPS) stimulation. Of note, leucine is not metabolized to integrate into the TCA cycle in basal or stimulated human macrophages. Surprisingly, the pharmacological inhibition of BCAT1 reduced glucose-derived itaconate, α-ketoglutarate and 2-hydroxyglutarate levels without affecting succinate and citrate levels, indicating a partial inhibition of the TCA cycle. This indirect effect is associated with NRF2 (also known as NFE2L2) activation and antioxidant responses. These results suggest a moonlighting role of BCAT1 through redox-mediated control of mitochondrial function during early macrophage activation. [ABSTRACT FROM AUTHOR]
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- 2020
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22. Comprehensive genomic profiles of small cell lung cancer
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Menon, Roopika, Korbel, Jan O., Chun, Sung-Min, Park, Kwon-Sik, Yang, Dian, Jahchan, Nadine S., Wilkerson, Matt, Müller, Christian, Karnezis, Anthony N., Cun, Yupeng, Michels, Sebastian, Dahmen, Ilona, Kim, Deokhoon, Vlasic, Ignacija, Hayes, Neil, George, Julie, Pützer, Brigitte, Wang, Maia Segura, Pinther, Berit, Fernández-Cuesta, Lynnette, Leenders, Frauke, Vaka, Dedeepya, Engelmann, David, Ozretić, Luka, Kong, Gu, Torres, Angela, Jang, Se Jin, Seidel, Danila, Lu, Xin, Bosco, Graziella, Lim, Jing Shan, and Bos, Marc
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neoplasms ,respiratory tract diseases - Abstract
We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Δex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.
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- 2015
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23. TAZ Interacts with TTF-1 and Regulates Expression of Surfactant Protein-C.
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Park, Kwon-Sik, Whitsett, Jeffrey A., Di Palma, Tina, Jeong-Ho Hong, Yaffe, Michael B., and Zannini, Mariastella
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PROTEINS , *GENE expression , *GENETIC regulation , *MESSENGER RNA , *EPITHELIAL cells , *LUNGS , *MICE , *GENETICS - Abstract
Thyroid transcription factor-1 (TTF-1/Nkx-2.1) is required for formation of the lung and differentiation of peripheral respiratory epithelial cells. TTF-1 activates transcription of target genes, including the surfactant proteins critical for lung function. A recently identified protein TAZ (transcriptional co-activator with PDZ -binding motif) contains a WW domain and a COOH-terminal PDZ-binding motif that are proposed to mediate its interactions with various transcriptional proteins. To determine the role of TAZ in the regulation of gene expression in the lung, the sites of TAZ expression and the role of TAZ in the regulation of respiratory epithelial gene expression were assessed. TAZ mRNA was detected in immortalized mouse lung epithelial cells, primary isolates of mouse alveolar type II epithelial cells, and epithelial cells of fetal lung. Sites of TAZ mRNA and protein overlapped with those of TTF-1 and surfactant protein C (SP-C) in the respiratory epithelial cells of the mouse lung. In the presence of TTF-1, TAZ synergistically activated the expression of mouse SP-C-luciferase reporter constructs. Mammalian two-hybrid assays and pull-down experiments demonstrated that the TAZ directly interacted with TTF-1. Further, deletion analysis demonstrated that TAZ binds to the NH2-terminal domain of TTF-1. TAZ binds to TTF-1, increasing the transcriptional activity of TTF-1 on the SP-C promoter. Developmental and cell-selective regulation of TAZ provides a mechanism by which the activity of TTF-1 on target genes is modulated. [ABSTRACT FROM AUTHOR]
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- 2004
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24. The H3K4 methyltransferase SETD1A is required for proliferation of non-small cell lung cancer cells by promoting S-phase progression.
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Kang, Joo-Young, Park, Jin Woo, Hwang, Yusang, Hahm, Ja Young, Park, Junyoung, Park, Kwon-Sik, and Seo, Sang-Beom
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NON-small-cell lung carcinoma , *CELL proliferation , *INHIBITION of cellular proliferation , *CANCER cells , *DNA replication , *EPIGENETICS - Abstract
Epigenetic dysregulation has been strongly implicated in carcinogenesis and is one of the mechanisms that contribute to the development of lung cancer. Using genome-wide CRISPR/Cas9 library screening, we showed SET domain-containing protein 1A (SETD1A) is an essential epigenetic modifier of the proliferation of NSCLC H1299 cells. Depletion of SETD1A strikingly inhibited the proliferation of NSCLC cells. IHC staining and bioinformatics showed that SETD1A is upregulated in lung cancer. Kaplan-Meier survival analysis indicated that high expression of SETD1A is associated with poor prognosis of patients with NSCLC. We revealed that loss of SETD1A inhibits DNA replication and induces replication stress accompanied by impaired fork progression. In addition, transcription of CDC7 and TOP1, which are involved in replication origin activation and fork progression, respectively, was significantly reduced by knockdown of SETD1A. Taken together, these findings demonstrated SETD1A is a critical epigenetic modifier of NSCLC cell proliferation by promoting the transcription of a subset of DNA replication-associated genes. • SETD1A is an essential epigenetic modifier for proliferation of H1299 cells. • SETD1A knockdown impairs replication fork progression and induces replication stress. • SETD1A is required to transcription of S-phase associated target gene s via H3K4me3 methylation. [ABSTRACT FROM AUTHOR]
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- 2021
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25. Nfib Promotes Metastasis through a Widespread Increase in Chromatin Accessibility.
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Denny, Sarah K., Yang, Dian, Chuang, Chen-Hua, Brady, Jennifer J., Lim, Jing Shan, Grüner, Barbara M., Chiou, Shin-Heng, Schep, Alicia N., Baral, Jessika, Hamard, Cécile, Antoine, Martine, Wislez, Marie, Kong, Christina S., Connolly, Andrew J., Park, Kwon-Sik, Sage, Julien, Greenleaf, William J., and Winslow, Monte M.
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METASTASIS , *CANCER-related mortality , *CAUSES of death , *CHROMATIN , *CANCER invasiveness , *CANCER genetics , *LOCUS (Genetics) , *CELL populations - Abstract
Summary Metastases are the main cause of cancer deaths, but the mechanisms underlying metastatic progression remain poorly understood. We isolated pure populations of cancer cells from primary tumors and metastases from a genetically engineered mouse model of human small cell lung cancer (SCLC) to investigate the mechanisms that drive the metastatic spread of this lethal cancer. Genome-wide characterization of chromatin accessibility revealed the opening of large numbers of distal regulatory elements across the genome during metastatic progression. These changes correlate with copy number amplification of the Nfib locus, and differentially accessible sites were highly enriched for Nfib transcription factor binding sites. Nfib is necessary and sufficient to increase chromatin accessibility at a large subset of the intergenic regions. Nfib promotes pro-metastatic neuronal gene expression programs and drives the metastatic ability of SCLC cells. The identification of widespread chromatin changes during SCLC progression reveals an unexpected global reprogramming during metastatic progression. [ABSTRACT FROM AUTHOR]
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- 2016
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26. Genetic disruption of ATAT1 causes RhoA downregulation through abnormal truncation of C/EBPβ.
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Choi JH, Jeong J, Kim J, You E, Keum S, Song S, Hwang YE, Ji M, Park KS, and Rhee S
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- Humans, Acetylation, Cathepsin L metabolism, Cathepsin L genetics, Cell Line, Tumor, Down-Regulation, Microtubules metabolism, Promoter Regions, Genetic genetics, Microtubule Proteins genetics, Microtubule Proteins metabolism, Acetyltransferases metabolism, Acetyltransferases genetics, CCAAT-Enhancer-Binding Protein-beta metabolism, CCAAT-Enhancer-Binding Protein-beta genetics, rhoA GTP-Binding Protein metabolism, rhoA GTP-Binding Protein genetics
- Abstract
Microtubule acetylation has been shown to regulate actin filament dynamics by modulating signaling pathways that control actin organization, although the precise mechanisms remain unknown. In this study, we found that the downregulation of microtubule acetylation via the disruption ATAT1 (which encodes α-tubulin N-acetyltransferase 1) inhibited the expression of RhoA, a small GTPase involved in regulating the organization of actin filaments and the formation of stress fibers. Analysis of RHOA promoter and chromatin immunoprecipitation assays revealed that C/EBPβ is a major regulator of RHOA expression. Interestingly, the majority of C/EBPβ in ATAT1 knockout (KO) cells was found in the nucleus as a 27-kDa fragment (referred to as C/EBPβp27) lacking the N-terminus of C/EBPβ. Overexpression of a gene encoding a C/EBPβp27-mimicking protein via an N-terminal deletion in C/EBPβ led to competitive binding with wild-type C/EBPβ at the C/EBPβ binding site in the RHOA promoter, resulting in a significant decrease of RHOA expression. We also found that cathepsin L (CTSL), which is overexpressed in ATAT1 KO cells, is responsible for C/EBPβp27 formation in the nucleus. Treatment with a CTSL inhibitor led to the restoration of RHOA expression by downregulation of C/EBPβp27 and the invasive ability of ATAT1 KO MDA-MB-231 breast cancer cells. Collectively, our findings suggest that the downregulation of microtubule acetylation associated with ATAT1 deficiency suppresses RHOA expression by forming C/EBPβp27 in the nucleus through CTSL. We propose that CTSL and C/EBPβp27 may represent a novel therapeutic target for breast cancer treatment. [BMB Reports 2024; 57(6): 293-298].
- Published
- 2024
27. CRACD loss promotes small cell lung cancer tumorigenesis via EZH2-mediated immune evasion.
- Author
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Zhang S, Kim KB, Huang Y, Kim DW, Kim B, Ko KP, Zou G, Zhang J, Jun S, Kirk NA, Hwang YE, Ban YH, Chan JM, Rudin CM, Park KS, and Park JI
- Abstract
The mechanisms underlying immune evasion and immunotherapy resistance in small cell lung cancer (SCLC) remain unclear. Herein, we investigate the role of CRACD tumor suppressor in SCLC. We found that CRACD is frequently inactivated in SCLC, and Cracd knockout (KO) significantly accelerates SCLC development driven by loss of Rb1 , Trp53 , and Rbl2 . Notably, the Cracd-deficient SCLC tumors display CD8+ T cell depletion and suppression of antigen presentation pathway. Mechanistically, CRACD loss silences the MHC-I pathway through EZH2. EZH2 blockade is sufficient to restore the MHC-I pathway and inhibit CRACD loss-associated SCLC tumorigenesis. Unsupervised single-cell transcriptomic analysis identifies SCLC patient tumors with concomitant inactivation of CRACD, impairment of tumor antigen presentation, and downregulation of EZH2 target genes. Our findings define CRACD loss as a new molecular signature associated with immune evasion of SCLC cells and proposed EZH2 blockade as a viable option for CRACD-negative SCLC treatment., Competing Interests: Competing Interest Statement: The authors declare that they have no conflict of competing interests.
- Published
- 2023
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28. CRACD suppresses neuroendocrinal plasticity of lung adenocarcinoma.
- Author
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Kim B, Zhang S, Huang Y, Ko KP, Zou G, Zhang J, Jun S, Kim KB, Jung YS, Park KS, and Park JI
- Abstract
Tumor cell plasticity contributes to intratumoral heterogeneity and therapy resistance. Through cell plasticity, lung adenocarcinoma (LUAD) cells transform into neuroendocrinal (NE) tumor cells. However, the mechanisms of NE cell plasticity remain unclear. CRACD, a capping protein inhibitor, is frequently inactivated in cancers. CRACD knock-out (KO) de-represses NE-related gene expression in the pulmonary epithelium and LUAD cells. In LUAD mouse models, Cracd KO increases intratumoral heterogeneity with NE gene expression. Single-cell transcriptomic analysis showed that Cracd KO-induced NE plasticity is associated with cell de-differentiation and activated stemness-related pathways. The single-cell transcriptomes of LUAD patient tumors recapitulate that the distinct LUAD NE cell cluster expressing NE genes is co-enriched with SOX2, OCT4, and NANOG pathway activation, and impaired actin remodeling. This study reveals an unexpected role of CRACD in restricting NE cell plasticity that induces cell de-differentiation, providing new insights into cell plasticity of LUAD., Competing Interests: Declaration of interests All authors declare that they have no competing interests.
- Published
- 2023
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29. WNT5A-RHOA Signaling Is a Driver of Tumorigenesis and Represents a Therapeutically Actionable Vulnerability in Small Cell Lung Cancer.
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Kim KB, Kim DW, Kim Y, Tang J, Kirk N, Gan Y, Kim B, Fang B, Park JL, Zheng Y, and Park KS
- Subjects
- Animals, Mice, beta Catenin metabolism, Wnt Signaling Pathway, Molecular Targeted Therapy, Carcinogenesis genetics, Lung Neoplasms genetics, rhoA GTP-Binding Protein genetics, rhoA GTP-Binding Protein metabolism, Small Cell Lung Carcinoma genetics, Wnt-5a Protein genetics, Wnt-5a Protein metabolism
- Abstract
WNT signaling represents an attractive target for cancer therapy due to its widespread oncogenic role. However, the molecular players involved in WNT signaling and the impact of their perturbation remain unknown for numerous recalcitrant cancers. Here, we characterize WNT pathway activity in small cell lung cancer (SCLC) and determine the functional role of WNT signaling using genetically engineered mouse models. β-Catenin, a master mediator of canonical WNT signaling, was dispensable for SCLC development, and its transcriptional program was largely silenced during tumor development. Conversely, WNT5A, a ligand for β-catenin-independent noncanonical WNT pathways, promoted neoplastic transformation and SCLC cell proliferation, whereas WNT5A deficiency inhibited SCLC development. Loss of p130 in SCLC cells induced expression of WNT5A, which selectively increased Rhoa transcription and activated RHOA protein to drive SCLC. Rhoa knockout suppressed SCLC development in vivo, and chemical perturbation of RHOA selectively inhibited SCLC cell proliferation. These findings suggest a novel requirement for the WNT5A-RHOA axis in SCLC, providing critical insights for the development of novel therapeutic strategies for this recalcitrant cancer. This study also sheds light on the heterogeneity of WNT signaling in cancer and the molecular determinants of its cell-type specificity., Significance: The p130-WNT5A-RHOA pathway drives SCLC progression and is a potential target for the development of therapeutic interventions and biomarkers to improve patient treatment., (©2022 American Association for Cancer Research.)
- Published
- 2022
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30. KIX domain determines a selective tumor-promoting role for EP300 and its vulnerability in small cell lung cancer.
- Author
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Kim KB, Kabra A, Kim DW, Xue Y, Huang Y, Hou PC, Zhou Y, Miranda LJ, Park JI, Shi X, Bender TP, Bushweller JH, and Park KS
- Subjects
- Animals, E1A-Associated p300 Protein, Mice, Protein Binding, Transcription Factors metabolism, Lung Neoplasms genetics, Small Cell Lung Carcinoma genetics
- Abstract
EP300, a transcription coactivator important in proliferation and differentiation, is frequently mutated in diverse cancer types, including small cell lung cancer (SCLC). While these mutations are thought to result in loss of EP300 function, the impact on tumorigenesis remains largely unknown. Here, we demonstrate that EP300 mutants lacking acetyltransferase domain accelerate tumor development in mouse models of SCLC. However, unexpectedly, complete Ep300 knockout suppresses SCLC development and proliferation. Dissection of EP300 domains identified kinase inducible domain-interacting (KIX) domain, specifically its interaction with transcription factors including MYB, as the determinant of protumorigenic activity. Ala
627 in EP300 KIX results in a higher protein-binding affinity than Asp647 at the equivalent position in CREBBP KIX, underlying the selectivity of KIX-binding partners for EP300. Blockade of KIX-mediated interactions inhibits SCLC development in mice and cell growth. This study unravels domain-specific roles for EP300 in SCLC and unique vulnerability of the EP300 KIX domain for therapeutic intervention.- Published
- 2022
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31. Fragmentation of Small-Cell Lung Cancer Regulatory States in Heterotypic Microenvironments.
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Schaff DL, Singh S, Kim KB, Sutcliffe MD, Park KS, and Janes KA
- Subjects
- Animals, Female, Humans, Lung, Mice, Neoplasm Recurrence, Local, Tumor Microenvironment, Breast Neoplasms, Lung Neoplasms genetics, Small Cell Lung Carcinoma genetics
- Abstract
Small-cell lung cancers derive from pulmonary neuroendocrine cells, which have stem-like properties to reprogram into other cell types upon lung injury. It is difficult to uncouple transcriptional plasticity of these transformed cells from genetic changes that evolve in primary tumors or secondary metastases. Profiling of single cells is also problematic if the required sample dissociation activates injury-like signaling and reprogramming. Here we defined cell-state heterogeneities in situ through laser capture microdissection-based 10-cell transcriptomics coupled with stochastic-profiling fluctuation analysis. In labeled cells from a small-cell lung cancer mouse model initiated by neuroendocrine deletion of Rb1 - Trp53 , variations in transcript abundance revealed cell-to-cell differences in regulatory state in vitro and in vivo . Fluctuating transcripts in spheroid culture were partly shared among Rb1 - Trp53 -null models, and heterogeneities increased considerably when cells were delivered intravenously to colonize the liver. Colonization of immunocompromised animals drove a fractional appearance of alveolar type II-like markers and poised cells for paracrine stimulation from immune cells and hepatocytes. Immunocompetency further exaggerated the fragmentation of tumor states in the liver, yielding mixed stromal signatures evident in bulk sequencing from autochthonous tumors and metastases. Dozens of transcript heterogeneities recurred irrespective of biological context; their mapped orthologs brought together observations of murine and human small-cell lung cancer. Candidate heterogeneities recurrent in the liver also stratified primary human tumors into discrete groups not readily explained by molecular subtype but with prognostic relevance. These data suggest that heterotypic interactions in the liver and lung are an accelerant for intratumor heterogeneity in small-cell lung cancer. SIGNIFICANCE: These findings demonstrate that the single-cell regulatory heterogeneity of small-cell lung cancer becomes increasingly elaborate in the liver, a common metastatic site for the disease. See related articles by Singh and colleagues, p. 1840 and Sutcliffe and colleagues, p. 1868 ., (©2021 American Association for Cancer Research.)
- Published
- 2021
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32. BCAT1 affects mitochondrial metabolism independently of leucine transamination in activated human macrophages.
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Ko JH, Olona A, Papathanassiu AE, Buang N, Park KS, Costa ASH, Mauro C, Frezza C, and Behmoaras J
- Subjects
- Citric Acid Cycle, Humans, Leucine metabolism, Macrophage Activation, Macrophages metabolism, Mitochondria metabolism, Transaminases metabolism
- Abstract
In response to environmental stimuli, macrophages change their nutrient consumption and undergo an early metabolic adaptation that progressively shapes their polarization state. During the transient, early phase of pro-inflammatory macrophage activation, an increase in tricarboxylic acid (TCA) cycle activity has been reported, but the relative contribution of branched-chain amino acid (BCAA) leucine remains to be determined. Here, we show that glucose but not glutamine is a major contributor of the increase in TCA cycle metabolites during early macrophage activation in humans. We then show that, although uptake of BCAAs is not altered, their transamination by BCAT1 is increased following 8 h lipopolysaccharide (LPS) stimulation. Of note, leucine is not metabolized to integrate into the TCA cycle in basal or stimulated human macrophages. Surprisingly, the pharmacological inhibition of BCAT1 reduced glucose-derived itaconate, α-ketoglutarate and 2-hydroxyglutarate levels without affecting succinate and citrate levels, indicating a partial inhibition of the TCA cycle. This indirect effect is associated with NRF2 (also known as NFE2L2) activation and anti-oxidant responses. These results suggest a moonlighting role of BCAT1 through redox-mediated control of mitochondrial function during early macrophage activation., Competing Interests: Competing interestsA.E.P. is an employee of Ergon Pharmaceuticals Ltd. The remaining authors declare no competing financial interests., (© 2020. Published by The Company of Biologists Ltd.)
- Published
- 2020
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33. FGFR1 Is Critical for RBL2 Loss-Driven Tumor Development and Requires PLCG1 Activation for Continued Growth of Small Cell Lung Cancer.
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Kim KB, Kim Y, Rivard CJ, Kim DW, and Park KS
- Subjects
- Animals, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Disease Progression, Female, Gene Deletion, Genes, Regulator, Genes, Retinoblastoma, Humans, Lung Neoplasms etiology, Lung Neoplasms genetics, Lung Neoplasms metabolism, Male, Mice, Mice, Knockout, Neoplasm Proteins genetics, Neuroendocrine Cells metabolism, Neuroendocrine Cells pathology, Phospholipase C gamma antagonists & inhibitors, Precancerous Conditions metabolism, Precancerous Conditions pathology, Receptor, Fibroblast Growth Factor, Type 1 genetics, Retinoblastoma-Like Protein p130 genetics, Small Cell Lung Carcinoma etiology, Small Cell Lung Carcinoma genetics, Small Cell Lung Carcinoma metabolism, Lung Neoplasms pathology, Neoplasm Proteins metabolism, Phospholipase C gamma metabolism, Receptor, Fibroblast Growth Factor, Type 1 metabolism, Retinoblastoma-Like Protein p130 metabolism, Small Cell Lung Carcinoma pathology
- Abstract
Small cell lung cancer (SCLC) remains a recalcitrant disease where limited therapeutic options have not improved overall survival, and approved targeted therapies are lacking. Amplification of the tyrosine kinase receptor FGFR1 (fibroblast growth factor receptor 1) is one of the few actionable alterations found in the SCLC genome. However, efforts to develop targeted therapies for FGFR1 -amplified SCLC are hindered by critical gaps in knowledge around the molecular origins and mediators of FGFR1-driven signaling as well as the physiologic impact of targeting FGFR1. Here we show that increased FGFR1 promotes tumorigenic progression in precancerous neuroendocrine cells and is required for SCLC development in vivo . Notably, Fgfr1 knockout suppressed tumor development in a mouse model lacking the retinoblastoma-like protein 2 ( Rbl2 ) tumor suppressor gene but did not affect a model with wild-type Rbl2 . In support of a functional interaction between these two genes, loss of RBL2 induced FGFR1 expression and restoration of RBL2 repressed it, suggesting a novel role for RBL2 as a regulator of FGFR1 in SCLC. Additionally, FGFR1 activated phospholipase C gamma 1 (PLCG1), whereas chemical inhibition of PLCG1 suppressed SCLC growth, implicating PLCG1 as an effector of FGFR1 signaling in SCLC. Collectively, this study uncovers mechanisms underlying FGFR1-driven SCLC that involve RBL2 upstream and PLCG1 downstream, thus providing potential biomarkers for anti-FGFR1 therapy. SIGNIFICANCE: This study identifies RBL2 and PLCG1 as critical components of amplified FGFR1 signaling in SCLC, thus representing potential targets for biomarker analysis and therapeutic development in this disease., (©2020 American Association for Cancer Research.)
- Published
- 2020
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34. A trans-eQTL network regulates osteoclast multinucleation and bone mass.
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Pereira M, Ko JH, Logan J, Protheroe H, Kim KB, Tan ALM, Croucher PI, Park KS, Rotival M, Petretto E, Bassett JD, Williams GR, and Behmoaras J
- Subjects
- Animals, Female, Male, Mice genetics, Mice physiology, Mice, Knockout, Rats genetics, Rats physiology, Rats, Inbred Lew, Rats, Inbred WKY, Bone Density genetics, Bone Resorption genetics, Gene Regulatory Networks, Genome-Wide Association Study, Osteoclasts physiology, Quantitative Trait Loci physiology
- Abstract
Functional characterisation of cell-type-specific regulatory networks is key to establish a causal link between genetic variation and phenotype. The osteoclast offers a unique model for interrogating the contribution of co-regulated genes to in vivo phenotype as its multinucleation and resorption activities determine quantifiable skeletal traits. Here we took advantage of a trans -regulated gene network (MMnet, macrophage multinucleation network) which we found to be significantly enriched for GWAS variants associated with bone-related phenotypes. We found that the network hub gene Bcat1 and seven other co-regulated MMnet genes out of 13, regulate bone function. Specifically, global ( Pik3cb
-/- , Atp8b2+/- , Igsf8-/- , Eml1-/- , Appl2-/- , Deptor-/- ) and myeloid-specific Slc40a1 knockout mice displayed abnormal bone phenotypes. We report opposing effects of MMnet genes on bone mass in mice and osteoclast multinucleation/resorption in humans with strong correlation between the two. These results identify MMnet as a functionally conserved network that regulates osteoclast multinucleation and bone mass., Competing Interests: MP, JK, JL, HP, KK, AT, PC, KP, MR, EP, JB, GW, JB No competing interests declared, (© 2020, Pereira et al.)- Published
- 2020
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35. Crebbp Loss Drives Small Cell Lung Cancer and Increases Sensitivity to HDAC Inhibition.
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Jia D, Augert A, Kim DW, Eastwood E, Wu N, Ibrahim AH, Kim KB, Dunn CT, Pillai SPS, Gazdar AF, Bolouri H, Park KS, and MacPherson D
- Subjects
- Acetylation, Animals, Cell Movement, Cell Proliferation, Cell Transformation, Neoplastic, Epithelial-Mesenchymal Transition, Gene Expression Regulation, Neoplastic, Histone Deacetylase Inhibitors pharmacology, Humans, Lung Neoplasms drug therapy, Lung Neoplasms metabolism, Mice, Mice, Knockout, Mutation, Small Cell Lung Carcinoma drug therapy, Small Cell Lung Carcinoma metabolism, Tumor Cells, Cultured, CREB-Binding Protein physiology, Drug Resistance, Neoplasm, Histone Deacetylases chemistry, Lung Neoplasms pathology, Retinoblastoma Protein physiology, Small Cell Lung Carcinoma pathology, Tumor Suppressor Protein p53 physiology
- Abstract
CREBBP , encoding an acetyltransferase, is among the most frequently mutated genes in small cell lung cancer (SCLC), a deadly neuroendocrine tumor type. We report acceleration of SCLC upon Crebbp inactivation in an autochthonous mouse model. Extending these observations beyond the lung, broad Crebbp deletion in mouse neuroendocrine cells cooperated with Rb1/Trp53 loss to promote neuroendocrine thyroid and pituitary carcinomas. Gene expression analyses showed that Crebbp loss results in reduced expression of tight junction and cell adhesion genes, including Cdh1 , across neuroendocrine tumor types, whereas suppression of Cdh1 promoted transformation in SCLC. CDH1 and other adhesion genes exhibited reduced histone acetylation with Crebbp inactivation. Treatment with the histone deacetylase (HDAC) inhibitor Pracinostat increased histone acetylation and restored CDH1 expression. In addition, a subset of Rb1/Trp53/Crebbp -deficient SCLC exhibited exceptional responses to Pracinostat in vivo Thus, CREBBP acts as a potent tumor suppressor in SCLC, and inactivation of CREBBP enhances responses to a targeted therapy. Significance: Our findings demonstrate that CREBBP loss in SCLC reduces histone acetylation and transcription of cellular adhesion genes, while driving tumorigenesis. These effects can be partially restored by HDAC inhibition, which exhibited enhanced effectiveness in Crebbp -deleted tumors. These data provide a rationale for selectively treating CREBBP -mutant SCLC with HDAC inhibitors. Cancer Discov; 8(11); 1422-37. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1333 ., (©2018 American Association for Cancer Research.)
- Published
- 2018
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36. A Novel, Fully Human Anti-fucosyl-GM1 Antibody Demonstrates Potent In Vitro and In Vivo Antitumor Activity in Preclinical Models of Small Cell Lung Cancer.
- Author
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Ponath P, Menezes D, Pan C, Chen B, Oyasu M, Strachan D, LeBlanc H, Sun H, Wang XT, Rangan VS, Deshpande S, Cristea S, Park KS, Sage J, and Cardarelli PM
- Subjects
- Animals, Antibody-Dependent Cell Cytotoxicity immunology, Antigens, Neoplasm immunology, Carcinoma, Small Cell drug therapy, Carcinoma, Small Cell metabolism, Carcinoma, Small Cell pathology, Cell Line, Tumor, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, G(M1) Ganglioside antagonists & inhibitors, G(M1) Ganglioside immunology, G(M1) Ganglioside metabolism, Humans, Immunohistochemistry, Immunomodulation drug effects, Lung Neoplasms drug therapy, Lung Neoplasms metabolism, Lung Neoplasms pathology, Mice, Protein Binding, Receptors, IgG metabolism, Tumor Necrosis Factor Receptor Superfamily, Member 9 antagonists & inhibitors, Xenograft Model Antitumor Assays, Antineoplastic Agents, Immunological pharmacology, G(M1) Ganglioside analogs & derivatives
- Abstract
Purpose: The ganglioside fucosyl-GM1 (FucGM1) is a tumor-associated antigen expressed in a large percentage of human small cell lung cancer (SCLC) tumors, but absent in most normal adult tissues, making it a promising target in immuno-oncology. This study was undertaken to evaluate the preclinical efficacy of BMS-986012, a novel, nonfucosylated, fully human IgG1 antibody that binds specifically to FucGM1. Experimental Design: The antitumor activity of BMS-986012 was evaluated in in vitro assays using SCLC cells and in mouse xenograft and syngeneic tumor models, with and without chemotherapeutic agents and checkpoint inhibitors. Results: BMS-986012 showed a high binding affinity for FcγRIIIa (CD16), which resulted in enhanced antibody-dependent cellular cytotoxicity (ADCC) against FucGM1-expressing tumor cell lines. BMS-986012-mediated tumor cell killing was also observed in complement-dependent cytotoxicity (CDC) and antibody-dependent cellular phagocytosis (ADCP) assays. In several mouse SCLC models, BMS-986012 demonstrated efficacy and was well tolerated. In the DMS79 xenograft model, tumor regression was achieved with BMS-986012 doses of 0.3 mg/kg and greater; antitumor activity was enhanced when BMS-986012 was combined with standard-of-care cisplatin or etoposide. In a syngeneic model, tumors derived from a genetically engineered model of SCLC were treated with BMS-986012 or anti-FucGM1 with a mouse IgG2a Fc and their responses evaluated; when BMS-986012 was combined with anti-PD-1 or anti-CD137 antibody, therapeutic responses significantly improved. Conclusions: Single-agent BMS-986012 demonstrated robust antitumor activity, with the addition of chemotherapeutic or immunomodulatory agents further inhibiting SCLC growth in the same models. These preclinical data supported evaluation of BMS-986012 in a phase I clinical trial of patients with relapsed, refractory SCLC. Clin Cancer Res; 24(20); 5178-89. ©2018 AACR ., (©2018 American Association for Cancer Research.)
- Published
- 2018
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37. Intertumoral Heterogeneity in SCLC Is Influenced by the Cell Type of Origin.
- Author
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Yang D, Denny SK, Greenside PG, Chaikovsky AC, Brady JJ, Ouadah Y, Granja JM, Jahchan NS, Lim JS, Kwok S, Kong CS, Berghoff AS, Schmitt A, Reinhardt HC, Park KS, Preusser M, Kundaje A, Greenleaf WJ, Sage J, and Winslow MM
- Subjects
- Animals, Cell Line, Tumor, Disease Models, Animal, Humans, Lung Neoplasms pathology, Mice, Small Cell Lung Carcinoma pathology, Lung Neoplasms genetics, Small Cell Lung Carcinoma genetics
- Abstract
The extent to which early events shape tumor evolution is largely uncharacterized, even though a better understanding of these early events may help identify key vulnerabilities in advanced tumors. Here, using genetically defined mouse models of small cell lung cancer (SCLC), we uncovered distinct metastatic programs attributable to the cell type of origin. In one model, tumors gain metastatic ability through amplification of the transcription factor NFIB and a widespread increase in chromatin accessibility, whereas in the other model, tumors become metastatic in the absence of NFIB-driven chromatin alterations. Gene-expression and chromatin accessibility analyses identify distinct mechanisms as well as markers predictive of metastatic progression in both groups. Underlying the difference between the two programs was the cell type of origin of the tumors, with NFIB-independent metastases arising from mature neuroendocrine cells. Our findings underscore the importance of the identity of cell type of origin in influencing tumor evolution and metastatic mechanisms. Significance: We show that SCLC can arise from different cell types of origin, which profoundly influences the eventual genetic and epigenetic changes that enable metastatic progression. Understanding intertumoral heterogeneity in SCLC, and across cancer types, may illuminate mechanisms of tumor progression and uncover how the cell type of origin affects tumor evolution. Cancer Discov; 8(10); 1316-31. ©2018 AACR. See related commentary by Pozo et al., p. 1216 This article is highlighted in the In This Issue feature, p. 1195 ., (©2018 American Association for Cancer Research.)
- Published
- 2018
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38. Transcriptional deregulation underlying the pathogenesis of small cell lung cancer.
- Author
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Kim DW, Kim KC, Kim KB, Dunn CT, and Park KS
- Abstract
The discovery of recurrent alterations in genes encoding transcription regulators and chromatin modifiers is one of the most important recent developments in the study of the small cell lung cancer (SCLC) genome. With advances in models and analytical methods, the field of SCLC biology has seen remarkable progress in understanding the deregulated transcription networks linked to the tumor development and malignant progression. This review will discuss recent discoveries on the roles of RB and P53 family of tumor suppressors and MYC family of oncogenes in tumor initiation and development. It will also describe the roles of lineage-specific factors in neuroendocrine (NE) cell differentiation and homeostasis and the roles of epigenetic alterations driven by changes in NFIB and chromatin modifiers in malignant progression and chemoresistance. These recent findings have led to a model of transcriptional network in which multiple pathways converge on regulatory regions of crucial genes linked to tumor development. Validation of this model and characterization of target genes will provide critical insights into the biology of SCLC and novel strategies for tumor intervention., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.
- Published
- 2018
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39. Genetic requirement for Mycl and efficacy of RNA Pol I inhibition in mouse models of small cell lung cancer.
- Author
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Kim DW, Wu N, Kim YC, Cheng PF, Basom R, Kim D, Dunn CT, Lee AY, Kim K, Lee CS, Singh A, Gazdar AF, Harris CR, Eisenman RN, Park KS, and MacPherson D
- Subjects
- Animals, Animals, Genetically Modified, Benzothiazoles pharmacology, Disease Models, Animal, Enzyme Activation drug effects, Enzyme Inhibitors pharmacology, Gene Silencing, Lung Neoplasms physiopathology, Mice, Naphthyridines pharmacology, Proto-Oncogene Proteins c-myc genetics, RNA Polymerase I antagonists & inhibitors, Ribosomes metabolism, Small Cell Lung Carcinoma physiopathology, Tumor Burden drug effects, Tumor Cells, Cultured, Lung Neoplasms enzymology, Lung Neoplasms genetics, Proto-Oncogene Proteins c-myc metabolism, RNA Polymerase I metabolism, Small Cell Lung Carcinoma enzymology, Small Cell Lung Carcinoma genetics
- Abstract
Small cell lung cancer (SCLC) is a devastating neuroendocrine carcinoma. MYCL (L-Myc) is frequently amplified in human SCLC, but its roles in SCLC progression are poorly understood. We isolated preneoplastic neuroendocrine cells from a mouse model of SCLC and found that ectopic expression of L-Myc, c-Myc, or N-Myc conferred tumor-forming capacity. We focused on L-Myc, which promoted pre-rRNA synthesis and transcriptional programs associated with ribosomal biogenesis. Deletion of Mycl in two genetically engineered models of SCLC resulted in strong suppression of SCLC. The high degree of suppression suggested that L-Myc may constitute a therapeutic target for a broad subset of SCLC. We then used an RNA polymerase I inhibitor to target rRNA synthesis in an autochthonous Rb/p53-deleted mouse SCLC model and found significant tumor inhibition. These data reveal that activation of RNA polymerase I by L-Myc and other MYC family proteins provides an axis of vulnerability for this recalcitrant cancer., (© 2016 Kim et al.; Published by Cold Spring Harbor Laboratory Press.)
- Published
- 2016
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40. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer.
- Author
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Peifer M, Fernández-Cuesta L, Sos ML, George J, Seidel D, Kasper LH, Plenker D, Leenders F, Sun R, Zander T, Menon R, Koker M, Dahmen I, Müller C, Di Cerbo V, Schildhaus HU, Altmüller J, Baessmann I, Becker C, de Wilde B, Vandesompele J, Böhm D, Ansén S, Gabler F, Wilkening I, Heynck S, Heuckmann JM, Lu X, Carter SL, Cibulskis K, Banerji S, Getz G, Park KS, Rauh D, Grütter C, Fischer M, Pasqualucci L, Wright G, Wainer Z, Russell P, Petersen I, Chen Y, Stoelben E, Ludwig C, Schnabel P, Hoffmann H, Muley T, Brockmann M, Engel-Riedel W, Muscarella LA, Fazio VM, Groen H, Timens W, Sietsma H, Thunnissen E, Smit E, Heideman DA, Snijders PJ, Cappuzzo F, Ligorio C, Damiani S, Field J, Solberg S, Brustugun OT, Lund-Iversen M, Sänger J, Clement JH, Soltermann A, Moch H, Weder W, Solomon B, Soria JC, Validire P, Besse B, Brambilla E, Brambilla C, Lantuejoul S, Lorimier P, Schneider PM, Hallek M, Pao W, Meyerson M, Sage J, Shendure J, Schneider R, Büttner R, Wolf J, Nürnberg P, Perner S, Heukamp LC, Brindle PK, Haas S, and Thomas RK
- Subjects
- Amino Acid Substitution, Animals, CREB-Binding Protein genetics, Cell Line, Tumor, DNA Copy Number Variations, DNA Mutational Analysis, E1A-Associated p300 Protein genetics, Gene Expression Profiling, Gene Regulatory Networks, Genome-Wide Association Study, Histone-Lysine N-Methyltransferase, Humans, Intercellular Signaling Peptides and Proteins genetics, Mice, Mice, Knockout, Models, Molecular, Mutation, Myeloid-Lymphoid Leukemia Protein genetics, Nerve Tissue Proteins genetics, Oligonucleotide Array Sequence Analysis, PTEN Phosphohydrolase genetics, Polymorphism, Single Nucleotide, Protein Processing, Post-Translational genetics, Retinoblastoma Protein genetics, Tumor Suppressor Protein p53 genetics, Genome, Human, Lung Neoplasms genetics, Small Cell Lung Carcinoma genetics
- Abstract
Small-cell lung cancer (SCLC) is an aggressive lung tumor subtype with poor prognosis. We sequenced 29 SCLC exomes, 2 genomes and 15 transcriptomes and found an extremely high mutation rate of 7.4±1 protein-changing mutations per million base pairs. Therefore, we conducted integrated analyses of the various data sets to identify pathogenetically relevant mutated genes. In all cases, we found evidence for inactivation of TP53 and RB1 and identified recurrent mutations in the CREBBP, EP300 and MLL genes that encode histone modifiers. Furthermore, we observed mutations in PTEN, SLIT2 and EPHA7, as well as focal amplifications of the FGFR1 tyrosine kinase gene. Finally, we detected many of the alterations found in humans in SCLC tumors from Tp53 and Rb1 double knockout mice. Our study implicates histone modification as a major feature of SCLC, reveals potentially therapeutically tractable genomic alterations and provides a generalizable framework for the identification of biologically relevant genes in the context of high mutational background.
- Published
- 2012
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41. Characterization of the cell of origin for small cell lung cancer.
- Author
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Park KS, Liang MC, Raiser DM, Zamponi R, Roach RR, Curtis SJ, Walton Z, Schaffer BE, Roake CM, Zmoos AF, Kriegel C, Wong KK, Sage J, and Kim CF
- Subjects
- Animals, Epithelium, Mice, Mice, Transgenic, Sequence Deletion, Genes, Retinoblastoma genetics, Lung Neoplasms genetics, Lung Neoplasms pathology, Neuroendocrine Cells pathology, Small Cell Lung Carcinoma genetics, Small Cell Lung Carcinoma pathology, Tumor Suppressor Protein p53 genetics
- Abstract
Small cell lung carcinoma (SCLC) is a neuroendocrine subtype of lung cancer that affects more than 200,000 people worldwide every year with a very high mortality rate. Here, we used a mouse genetics approach to characterize the cell of origin for SCLC; in this mouse model, tumors are initiated by the deletion of the Rb and p53 tumor suppressor genes in the lung epithelium of adult mice. We found that mouse SCLCs often arise in the lung epithelium, where neuroendocrine cells are located, and that the majority of early lesions were composed of proliferating neuroendocrine cells. In addition, mice in which Rb and p53 are deleted in a variety of non-neuroendocrine lung epithelial cells did not develop SCLC. These data indicate that SCLC likely arises from neuroendocrine cells in the lung.
- Published
- 2011
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42. Loss of p130 accelerates tumor development in a mouse model for human small-cell lung carcinoma.
- Author
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Schaffer BE, Park KS, Yiu G, Conklin JF, Lin C, Burkhart DL, Karnezis AN, Sweet-Cordero EA, and Sage J
- Subjects
- Animals, Biomarkers, Tumor genetics, Gene Expression Profiling, Humans, Integrases metabolism, Lung Neoplasms genetics, Lung Neoplasms metabolism, Mice, Mice, Knockout, Mice, Nude, Oligonucleotide Array Sequence Analysis, Prognosis, Small Cell Lung Carcinoma genetics, Small Cell Lung Carcinoma metabolism, Biomarkers, Tumor metabolism, Lung Neoplasms pathology, Retinoblastoma Protein physiology, Retinoblastoma-Like Protein p130 physiology, Small Cell Lung Carcinoma pathology, Tumor Suppressor Protein p53 physiology
- Abstract
Small-cell lung carcinoma (SCLC) is a neuroendocrine subtype of lung cancer. Although SCLC patients often initially respond to therapy, tumors nearly always recur, resulting in a 5-year survival rate of less than 10%. A mouse model has been developed based on the fact that the RB and p53 tumor suppressor genes are mutated in more than 90% of human SCLCs. Emerging evidence in patients and mouse models suggests that p130, a gene related to RB, may act as a tumor suppressor in SCLC cells. To test this idea, we used conditional mutant mice to delete p130 in combination with Rb and p53 in adult lung epithelial cells. We found that loss of p130 resulted in increased proliferation and significant acceleration of SCLC development in this triple-knockout mouse model. The histopathologic features of the triple-mutant mouse tumors closely resembled that of human SCLC. Genome-wide expression profiling experiments further showed that Rb/p53/p130-mutant mouse tumors were similar to human SCLC. These findings indicate that p130 plays a key tumor suppressor role in SCLC. Rb/p53/p130-mutant mice provide a novel preclinical mouse model to identify novel therapeutic targets against SCLC., ((c)2010 AACR.)
- Published
- 2010
- Full Text
- View/download PDF
43. GP130-STAT3 regulates epithelial cell migration and is required for repair of the bronchiolar epithelium.
- Author
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Kida H, Mucenski ML, Thitoff AR, Le Cras TD, Park KS, Ikegami M, Müller W, and Whitsett JA
- Subjects
- Animals, Bronchi drug effects, Cells, Cultured, Cytokine Receptor gp130 genetics, Epithelial Cells drug effects, Lung physiology, Lung surgery, Mice, Mice, Transgenic, Naphthalenes toxicity, Regeneration, Respiratory Mucosa cytology, Respiratory Mucosa drug effects, STAT3 Transcription Factor genetics, Signal Transduction, Bronchi cytology, Cell Movement physiology, Cytokine Receptor gp130 physiology, Epithelial Cells physiology, STAT3 Transcription Factor physiology
- Abstract
Following injury, bronchiolar cells undergo rapid squamous metaplasia, followed by proliferation and re-establishment of the complex columnar epithelium that is characteristic of the normal airway. Mechanisms that regulate the repair of bronchiolar epithelium are of considerable relevance for understanding the pathogenesis of both acute and chronic lung diseases associated with airway remodeling. This study was designed to identify the role of the GP130-STAT3 signaling pathway during repair of the bronchiolar epithelium. STAT3 (signal transducer and activator of transcription 3) and GP130 (glycoprotein 130) were each selectively deleted from the pulmonary epithelial cells of transgenic mice in vivo, producing Stat3(Delta/Delta) and Gp130(Delta/Delta) mice, respectively. Airway injury was induced in adult mice by administration of naphthalene, a toxicant of nonciliated respiratory epithelial cells (Clara cells). Nuclear STAT3 staining was induced in bronchiolar epithelial cells following naphthalene-mediated injury in control (Stat3(flox/flox)) mice. Whereas nearly complete repair of the bronchiolar epithelium was observed in control mice within 13 days, restoration of cell shape, cell density, and the pattern of ciliated and nonciliated cells did not occur in the peripheral bronchioles of either Stat3(Delta/Delta) or Gp130(Delta/Delta) mice. Expression of dominant-negative STAT3 inhibited airway epithelial cell migration during repair in vitro; wild-type STAT3 expression activated such migration. In the present study, we show that GP130-STAT3 signaling functions in a cell-autonomous manner to restore cell shape and numbers required for repair of the bronchiolar epithelium following injury.
- Published
- 2008
- Full Text
- View/download PDF
44. Stat3 is required for cytoprotection of the respiratory epithelium during adenoviral infection.
- Author
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Matsuzaki Y, Xu Y, Ikegami M, Besnard V, Park KS, Hull WM, Wert SE, and Whitsett JA
- Subjects
- Adenoviridae Infections genetics, Adenoviridae Infections prevention & control, Animals, Apoptosis genetics, Apoptosis immunology, Caspase 3, Caspases metabolism, Cell Line, Gene Expression Regulation, Viral immunology, Genetic Predisposition to Disease, Humans, Intubation, Intratracheal, Lung enzymology, Lung virology, Mice, Mice, Knockout, Mice, Transgenic, Pulmonary Alveoli enzymology, Pulmonary Alveoli immunology, Pulmonary Alveoli pathology, Pulmonary Alveoli virology, Respiratory Mucosa enzymology, Respiratory Mucosa virology, STAT3 Transcription Factor deficiency, STAT3 Transcription Factor genetics, Up-Regulation genetics, Up-Regulation immunology, bcl-X Protein physiology, Adenoviridae Infections immunology, Adenoviridae Infections pathology, Cytoprotection immunology, Lung immunology, Lung pathology, Respiratory Mucosa immunology, Respiratory Mucosa pathology, STAT3 Transcription Factor physiology
- Abstract
The role of Stat3 in the maintenance of pulmonary homeostasis following adenoviral-mediated lung injury was assessed in vivo. Stat3 was selectively deleted from bronchiolar and alveolar epithelial cells in Stat3(DeltaDelta) mice. Although lung histology and function were unaltered by deletion of Stat3 in vivo, Stat3(DeltaDelta) mice were highly susceptible to lung injury caused by intratracheal administration of AV1-GFP, an early (E) region 1- and E3-deleted, nonproliferative adenovirus. Severe airspace enlargement, loss of alveolar septae, and sloughing of the bronchiolar epithelium were observed in Stat3(DeltaDelta) mice as early as 1 day after exposure to the virus. Although surfactant protein A, B, and C content and surfactant protein-B mRNA expression in Stat3(DeltaDelta) mice were similar, TUNEL staining and caspase-3 were increased in alveolar type II epithelial cells of Stat3(DeltaDelta) mice after exposure to virus. RNA microarray analysis of type II epithelial cells isolated from Stat3(DeltaDelta) mice demonstrated significant changes in expression of numerous genes, including those genes regulating apoptosis, supporting the concept that the susceptibility of Stat3-deficient mice to adenovirus was related to the role of Stat3 in the regulation of cell survival. AV1-Bcl-x(L), an E1- and E3-deleted, nonproliferative adenovirus expressing the antiapoptotic protein Bcl-x(L), protected Stat3(DeltaDelta) mice from adenoviral-induced lung injury. Adenoviral infection of the lungs of Stat3-deficient mice was associated with severe injury of the alveolar and bronchiolar epithelium. Thus, Stat3 plays a critical cytoprotective role that is required for epithelial cell survival and maintenance of alveolar structures during the early phases of pulmonary adenoviral infection.
- Published
- 2006
- Full Text
- View/download PDF
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