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51. Data from Dynamic Tumor Growth Patterns in a Novel Murine Model of Colorectal Cancer

Author

Paul Olson, Terrah J., primary, Hadac, Jamie N., primary, Sievers, Chelsie K., primary, Leystra, Alyssa A., primary, Deming, Dustin A., primary, Zahm, Christopher D., primary, Albrecht, Dawn M., primary, Nomura, Alice, primary, Nettekoven, Laura A., primary, Plesh, Lauren K., primary, Clipson, Linda, primary, Sullivan, Ruth, primary, Newton, Michael A., primary, Schelman, William R., primary, and Halberg, Richard B., primary

Published
2023
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52. Supplementary Table 1 from Dynamic Tumor Growth Patterns in a Novel Murine Model of Colorectal Cancer

Author

Paul Olson, Terrah J., primary, Hadac, Jamie N., primary, Sievers, Chelsie K., primary, Leystra, Alyssa A., primary, Deming, Dustin A., primary, Zahm, Christopher D., primary, Albrecht, Dawn M., primary, Nomura, Alice, primary, Nettekoven, Laura A., primary, Plesh, Lauren K., primary, Clipson, Linda, primary, Sullivan, Ruth, primary, Newton, Michael A., primary, Schelman, William R., primary, and Halberg, Richard B., primary

Published
2023
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53. Supplementary Figure 2 from Dynamic Tumor Growth Patterns in a Novel Murine Model of Colorectal Cancer

Author

Paul Olson, Terrah J., primary, Hadac, Jamie N., primary, Sievers, Chelsie K., primary, Leystra, Alyssa A., primary, Deming, Dustin A., primary, Zahm, Christopher D., primary, Albrecht, Dawn M., primary, Nomura, Alice, primary, Nettekoven, Laura A., primary, Plesh, Lauren K., primary, Clipson, Linda, primary, Sullivan, Ruth, primary, Newton, Michael A., primary, Schelman, William R., primary, and Halberg, Richard B., primary

Published
2023
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54. Supplementary Table 1 from Colon Tumors with the Simultaneous Induction of Driver Mutations in APC, KRAS, and PIK3CA Still Progress through the Adenoma-to-carcinoma Sequence

Author

Hadac, Jamie N., primary, Leystra, Alyssa A., primary, Paul Olson, Terrah J., primary, Maher, Molly E., primary, Payne, Susan N., primary, Yueh, Alexander E., primary, Schwartz, Alexander R., primary, Albrecht, Dawn M., primary, Clipson, Linda, primary, Pasch, Cheri A., primary, Matkowskyj, Kristina A., primary, Halberg, Richard B., primary, and Deming, Dustin A., primary

Published
2023
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55. Supplementary Figure S1 from MTORC1/2 Inhibition as a Therapeutic Strategy for PIK3CA Mutant Cancers

Author

Fricke, Stephanie L., primary, Payne, Susan N., primary, Favreau, Peter F., primary, Kratz, Jeremy D., primary, Pasch, Cheri A., primary, Foley, Tyler M., primary, Yueh, Alexander E., primary, Van De Hey, Dana R., primary, Depke, Mitchell G., primary, Korkos, Demetra P., primary, Sha, Gioia Chengcheng, primary, DeStefanis, Rebecca A., primary, Clipson, Linda, primary, Burkard, Mark E., primary, Lemmon, Kayla K., primary, Parsons, Benjamin M., primary, Kenny, Paraic A., primary, Matkowskyj, Kristina A., primary, Newton, Michael A., primary, Skala, Melissa C., primary, and Deming, Dustin A., primary

Published
2023
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56. Table S3 from Patient-Derived Cancer Organoid Cultures to Predict Sensitivity to Chemotherapy and Radiation

Author

Pasch, Cheri A., primary, Favreau, Peter F., primary, Yueh, Alexander E., primary, Babiarz, Christopher P., primary, Gillette, Amani A., primary, Sharick, Joe T., primary, Karim, Mohammad Rezaul, primary, Nickel, Kwangok P., primary, DeZeeuw, Alyssa K., primary, Sprackling, Carley M., primary, Emmerich, Philip B., primary, DeStefanis, Rebecca A., primary, Pitera, Rosabella T., primary, Payne, Susan N., primary, Korkos, Demetra P., primary, Clipson, Linda, primary, Walsh, Christine M., primary, Miller, Devon, primary, Carchman, Evie H., primary, Burkard, Mark E., primary, Lemmon, Kayla K., primary, Matkowskyj, Kristina A., primary, Newton, Michael A., primary, Ong, Irene M., primary, Bassetti, Michael F., primary, Kimple, Randall J., primary, Skala, Melissa C., primary, and Deming, Dustin A., primary

Published
2023
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57. Supplementary Data from Patient-Derived Cancer Organoid Cultures to Predict Sensitivity to Chemotherapy and Radiation

Author

Pasch, Cheri A., primary, Favreau, Peter F., primary, Yueh, Alexander E., primary, Babiarz, Christopher P., primary, Gillette, Amani A., primary, Sharick, Joe T., primary, Karim, Mohammad Rezaul, primary, Nickel, Kwangok P., primary, DeZeeuw, Alyssa K., primary, Sprackling, Carley M., primary, Emmerich, Philip B., primary, DeStefanis, Rebecca A., primary, Pitera, Rosabella T., primary, Payne, Susan N., primary, Korkos, Demetra P., primary, Clipson, Linda, primary, Walsh, Christine M., primary, Miller, Devon, primary, Carchman, Evie H., primary, Burkard, Mark E., primary, Lemmon, Kayla K., primary, Matkowskyj, Kristina A., primary, Newton, Michael A., primary, Ong, Irene M., primary, Bassetti, Michael F., primary, Kimple, Randall J., primary, Skala, Melissa C., primary, and Deming, Dustin A., primary

Published
2023
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58. Figure S1 from Patient-Derived Cancer Organoid Cultures to Predict Sensitivity to Chemotherapy and Radiation

Author

Pasch, Cheri A., primary, Favreau, Peter F., primary, Yueh, Alexander E., primary, Babiarz, Christopher P., primary, Gillette, Amani A., primary, Sharick, Joe T., primary, Karim, Mohammad Rezaul, primary, Nickel, Kwangok P., primary, DeZeeuw, Alyssa K., primary, Sprackling, Carley M., primary, Emmerich, Philip B., primary, DeStefanis, Rebecca A., primary, Pitera, Rosabella T., primary, Payne, Susan N., primary, Korkos, Demetra P., primary, Clipson, Linda, primary, Walsh, Christine M., primary, Miller, Devon, primary, Carchman, Evie H., primary, Burkard, Mark E., primary, Lemmon, Kayla K., primary, Matkowskyj, Kristina A., primary, Newton, Michael A., primary, Ong, Irene M., primary, Bassetti, Michael F., primary, Kimple, Randall J., primary, Skala, Melissa C., primary, and Deming, Dustin A., primary

Published
2023
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59. Data from Mice Expressing Activated PI3K Rapidly Develop Advanced Colon Cancer

Author

Leystra, Alyssa A., primary, Deming, Dustin A., primary, Zahm, Christopher D., primary, Farhoud, Mohammed, primary, Olson, Terrah J. Paul, primary, Hadac, Jamie N., primary, Nettekoven, Laura A., primary, Albrecht, Dawn M., primary, Clipson, Linda, primary, Sullivan, Ruth, primary, Washington, Mary Kay, primary, Torrealba, Jose R., primary, Weichert, Jamey P., primary, and Halberg, Richard B., primary

Published
2023
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62. Supplementary Movie from Mice Expressing Activated PI3K Rapidly Develop Advanced Colon Cancer

Author

Leystra, Alyssa A., primary, Deming, Dustin A., primary, Zahm, Christopher D., primary, Farhoud, Mohammed, primary, Olson, Terrah J. Paul, primary, Hadac, Jamie N., primary, Nettekoven, Laura A., primary, Albrecht, Dawn M., primary, Clipson, Linda, primary, Sullivan, Ruth, primary, Washington, Mary Kay, primary, Torrealba, Jose R., primary, Weichert, Jamey P., primary, and Halberg, Richard B., primary

Published
2023
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64. Supplementary Figures 1-7 from Mice Expressing Activated PI3K Rapidly Develop Advanced Colon Cancer

Author

Leystra, Alyssa A., primary, Deming, Dustin A., primary, Zahm, Christopher D., primary, Farhoud, Mohammed, primary, Olson, Terrah J. Paul, primary, Hadac, Jamie N., primary, Nettekoven, Laura A., primary, Albrecht, Dawn M., primary, Clipson, Linda, primary, Sullivan, Ruth, primary, Washington, Mary Kay, primary, Torrealba, Jose R., primary, Weichert, Jamey P., primary, and Halberg, Richard B., primary

Published
2023
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67. Supplementary Figure S3 from Colon Tumors with the Simultaneous Induction of Driver Mutations in APC, KRAS, and PIK3CA Still Progress through the Adenoma-to-carcinoma Sequence

Author

Dustin A. Deming, Richard B. Halberg, Kristina A. Matkowskyj, Cheri A. Pasch, Linda Clipson, Dawn M. Albrecht, Alexander R. Schwartz, Alexander E. Yueh, Susan N. Payne, Molly E. Maher, Terrah J. Paul Olson, Alyssa A. Leystra, and Jamie N. Hadac

Abstract

Colonoscopic images over time, whole mount image and H&E-stained section of a tumor from a Apcfl/fl Pik3cap110* mouse inoculated with Adeno-Cre that spontaneously decreased in size.

Published
2023
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68. Supplementary Figure S1 from MTORC1/2 Inhibition as a Therapeutic Strategy for PIK3CA Mutant Cancers

Author

Dustin A. Deming, Melissa C. Skala, Michael A. Newton, Kristina A. Matkowskyj, Paraic A. Kenny, Benjamin M. Parsons, Kayla K. Lemmon, Mark E. Burkard, Linda Clipson, Rebecca A. DeStefanis, Gioia Chengcheng Sha, Demetra P. Korkos, Mitchell G. Depke, Dana R. Van De Hey, Alexander E. Yueh, Tyler M. Foley, Cheri A. Pasch, Jeremy D. Kratz, Peter F. Favreau, Susan N. Payne, and Stephanie L. Fricke

Abstract

Supplementary Figure S1 presents the viability of SW48 and SW48PK cells after treatment with BEZ235 and TAK-228 at the 100-400nM concentrations.

Published
2023
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69. Supplementary Figure 2 from Dynamic Tumor Growth Patterns in a Novel Murine Model of Colorectal Cancer

Author

Richard B. Halberg, William R. Schelman, Michael A. Newton, Ruth Sullivan, Linda Clipson, Lauren K. Plesh, Laura A. Nettekoven, Alice Nomura, Dawn M. Albrecht, Christopher D. Zahm, Dustin A. Deming, Alyssa A. Leystra, Chelsie K. Sievers, Jamie N. Hadac, and Terrah J. Paul Olson

Abstract

PDF file - 30K, Relative gene expression is shown for three adenomas and three intramucosal carcinomas taken from the colons of DSS-treated F1 Min mice.

Published
2023
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70. Supplementary Figure Legends from Colon Tumors with the Simultaneous Induction of Driver Mutations in APC, KRAS, and PIK3CA Still Progress through the Adenoma-to-carcinoma Sequence

Author

Dustin A. Deming, Richard B. Halberg, Kristina A. Matkowskyj, Cheri A. Pasch, Linda Clipson, Dawn M. Albrecht, Alexander R. Schwartz, Alexander E. Yueh, Susan N. Payne, Molly E. Maher, Terrah J. Paul Olson, Alyssa A. Leystra, and Jamie N. Hadac

Abstract

Supplementary Figure Legends

Published
2023
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71. Supplementary Data from Dual PI3K/mTOR Inhibition in Colorectal Cancers with APC and PIK3CA Mutations

Author

Dustin A. Deming, Michael A. Newton, Kristina A. Matkowskyj, Molly E Maher, Linda Clipson, Demetra P Korkos, Dana R Van De Hey, Alex E. Yueh, Cheri A. Pasch, Susan N. Payne, and Tyler M Foley

Abstract

S1. AP spheroids were plated and allowed to mature for 48 hours. S2. To address the issue of potentially slower growth of the spheres with the largest initial sizes, a change-point analysis was performed. S3. AP mice were treated with control (A) or BEZ235 (B) for 14 days. S4. AP mice were treated with BEZ235 or control for 14 days. S5. AP spheroids were treated with NVP-BYL719, BEZ235, LY3023414, or control for 24 hours. S5. AP spheroids were treated with NVP-BYL719, BEZ235, LY3023414, or control for 24 hours. Supplementary Table S1. AP spheroids were treated with NVP-BYL719, GDC0941, BEZ235, LY3023414, or control for 48 hours. Supplemental Table S2. AP mice were treated with BEZ235, LY3023414 or control for 14 days.

Published
2023
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72. Supplementary Figure 1 from Dynamic Tumor Growth Patterns in a Novel Murine Model of Colorectal Cancer

Author

Richard B. Halberg, William R. Schelman, Michael A. Newton, Ruth Sullivan, Linda Clipson, Lauren K. Plesh, Laura A. Nettekoven, Alice Nomura, Dawn M. Albrecht, Christopher D. Zahm, Dustin A. Deming, Alyssa A. Leystra, Chelsie K. Sievers, Jamie N. Hadac, and Terrah J. Paul Olson

Abstract

PDF file - 54K, Panel A illustrates the colonoscopic surveillance protocol. Panel B shows the serial biopsy protocol.

Published
2023
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73. Supplementary Table 1 from Dynamic Tumor Growth Patterns in a Novel Murine Model of Colorectal Cancer

Author

Richard B. Halberg, William R. Schelman, Michael A. Newton, Ruth Sullivan, Linda Clipson, Lauren K. Plesh, Laura A. Nettekoven, Alice Nomura, Dawn M. Albrecht, Christopher D. Zahm, Dustin A. Deming, Alyssa A. Leystra, Chelsie K. Sievers, Jamie N. Hadac, and Terrah J. Paul Olson

Abstract

PDF file - 21K, Characteristics of F1 ApcMin/+ mice treated with 4% dextran sodium sulfate.

Published
2023
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74. Data from MTORC1/2 Inhibition as a Therapeutic Strategy for PIK3CA Mutant Cancers

Author

Dustin A. Deming, Melissa C. Skala, Michael A. Newton, Kristina A. Matkowskyj, Paraic A. Kenny, Benjamin M. Parsons, Kayla K. Lemmon, Mark E. Burkard, Linda Clipson, Rebecca A. DeStefanis, Gioia Chengcheng Sha, Demetra P. Korkos, Mitchell G. Depke, Dana R. Van De Hey, Alexander E. Yueh, Tyler M. Foley, Cheri A. Pasch, Jeremy D. Kratz, Peter F. Favreau, Susan N. Payne, and Stephanie L. Fricke

Abstract

PIK3CA mutations are common in clinical molecular profiling, yet an effective means to target these cancers has yet to be developed. MTORC1 inhibitors are often used off-label for patients with PIK3CA mutant cancers with only limited data to support this approach. Here we describe a cohort of patients treated with cancers possessing mutations activating the PI3K signaling cascade with minimal benefit to treatment with the MTORC1 inhibitor everolimus. Previously, we demonstrated that dual PI3K/mTOR inhibition could decrease proliferation, induce differentiation, and result in a treatment response in APC and PIK3CA mutant colorectal cancer. However, reactivation of AKT was identified, indicating that the majority of the benefit may be secondary to MTORC1/2 inhibition. TAK-228, an MTORC1/2 inhibitor, was compared with dual PI3K/mTOR inhibition using BEZ235 in murine colorectal cancer spheroids. A reduction in spheroid size was observed with TAK-228 and BEZ235 (−13% and −14%, respectively) compared with an increase of >200% in control (P < 0.001). These spheroids were resistant to MTORC1 inhibition. In transgenic mice possessing Pik3ca and Apc mutations, BEZ235 and TAK-228 resulted in a median reduction in colon tumor size of 19% and 20%, respectively, with control tumors having a median increase of 18% (P = 0.02 and 0.004, respectively). This response correlated with a decrease in the phosphorylation of 4EBP1 and RPS6. MTORC1/2 inhibition is sufficient to overcome resistance to everolimus and induce a treatment response in PIK3CA mutant colorectal cancers and deserves investigation in clinical trials and in future combination regimens.

Published
2023
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75. Data from Colon Tumors with the Simultaneous Induction of Driver Mutations in APC, KRAS, and PIK3CA Still Progress through the Adenoma-to-carcinoma Sequence

Author

Dustin A. Deming, Richard B. Halberg, Kristina A. Matkowskyj, Cheri A. Pasch, Linda Clipson, Dawn M. Albrecht, Alexander R. Schwartz, Alexander E. Yueh, Susan N. Payne, Molly E. Maher, Terrah J. Paul Olson, Alyssa A. Leystra, and Jamie N. Hadac

Abstract

Human colorectal cancers often possess multiple mutations, including three to six driver mutations per tumor. The timing of when these mutations occur during tumor development and progression continues to be debated. More advanced lesions carry a greater number of driver mutations, indicating that colon tumors might progress from adenomas to carcinomas through the stepwise accumulation of mutations following tumor initiation. However, mutations that have been implicated in tumor progression have been identified in normal-appearing epithelial cells of the colon, leaving the possibility that these mutations might be present before the initiation of tumorigenesis. We utilized mouse models of colon cancer to investigate whether tumorigenesis still occurs through the adenoma-to-carcinoma sequence when multiple mutations are present at the time of tumor initiation. To create a model in which tumors could concomitantly possess mutations in Apc, Kras, and Pik3ca, we developed a novel minimally invasive technique to administer an adenovirus expressing Cre recombinase to a focal region of the colon. Here, we demonstrate that the presence of these additional driver mutations at the time of tumor initiation results in increased tumor multiplicity and an increased rate of progression to invasive adenocarcinomas. These cancers can even metastasize to retroperitoneal lymph nodes or the liver. However, despite having as many as three concomitant driver mutations at the time of initiation, these tumors still proceed through the adenoma-to-carcinoma sequence. Cancer Prev Res; 8(10); 952–61. ©2015 AACR.

Published
2023
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76. Supplementary Table 1 from Colon Tumors with the Simultaneous Induction of Driver Mutations in APC, KRAS, and PIK3CA Still Progress through the Adenoma-to-carcinoma Sequence

Author

Dustin A. Deming, Richard B. Halberg, Kristina A. Matkowskyj, Cheri A. Pasch, Linda Clipson, Dawn M. Albrecht, Alexander R. Schwartz, Alexander E. Yueh, Susan N. Payne, Molly E. Maher, Terrah J. Paul Olson, Alyssa A. Leystra, and Jamie N. Hadac

Abstract

Characteristics of the mice treated with Adeno-Cre.

Published
2023
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77. Supplementary Table 2 from Dynamic Tumor Growth Patterns in a Novel Murine Model of Colorectal Cancer

Author

Richard B. Halberg, William R. Schelman, Michael A. Newton, Ruth Sullivan, Linda Clipson, Lauren K. Plesh, Laura A. Nettekoven, Alice Nomura, Dawn M. Albrecht, Christopher D. Zahm, Dustin A. Deming, Alyssa A. Leystra, Chelsie K. Sievers, Jamie N. Hadac, and Terrah J. Paul Olson

Abstract

PDF file - 42K, Complete list of differentially expressed genes between intramucosal carcinomas and adenomas.

Published
2023
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78. Data from Dynamic Tumor Growth Patterns in a Novel Murine Model of Colorectal Cancer

Author

Richard B. Halberg, William R. Schelman, Michael A. Newton, Ruth Sullivan, Linda Clipson, Lauren K. Plesh, Laura A. Nettekoven, Alice Nomura, Dawn M. Albrecht, Christopher D. Zahm, Dustin A. Deming, Alyssa A. Leystra, Chelsie K. Sievers, Jamie N. Hadac, and Terrah J. Paul Olson

Abstract

Colorectal cancer often arises from adenomatous colonic polyps. Polyps can grow and progress to cancer, but may also remain static in size, regress, or resolve. Predicting which polyps progress and which remain benign is difficult. We developed a novel long-lived murine model of colorectal cancer with tumors that can be followed by colonoscopy. Our aim was to assess whether these tumors have similar growth patterns and histologic fates to human colorectal polyps to identify features to aid in risk stratification of colonic tumors. Long-lived ApcMin/+ mice were treated with dextran sodium sulfate to promote colonic tumorigenesis. Tumor growth patterns were characterized by serial colonoscopy with biopsies obtained for immunohistochemistry and gene expression profiling. Tumors grew, remained static, regressed, or resolved over time with different relative frequencies. Newly developed tumors demonstrated higher rates of growth and resolution than more established tumors that tended to remain static in size. Colonic tumors were hyperplastic lesions (3%), adenomas (73%), intramucosal carcinomas (20%), or adenocarcinomas (3%). Interestingly, the level of β-catenin was higher in adenomas that became intratumoral carcinomas than those that failed to progress. In addition, differentially expressed genes between adenomas and intramucosal carcinomas were identified. This novel murine model of intestinal tumorigenesis develops colonic tumors that can be monitored by serial colonoscopy, mirror growth patterns seen in human colorectal polyps, and progress to colorectal cancer. Further characterization of cellular and molecular features is needed to determine which features can be used to risk-stratify polyps for progression to colorectal cancer and potentially guide prevention strategies. Cancer Prev Res; 7(1); 105–13. ©2013 AACR.

Published
2023
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79. Supplementary Table 3 from Dynamic Tumor Growth Patterns in a Novel Murine Model of Colorectal Cancer

Author

Richard B. Halberg, William R. Schelman, Michael A. Newton, Ruth Sullivan, Linda Clipson, Lauren K. Plesh, Laura A. Nettekoven, Alice Nomura, Dawn M. Albrecht, Christopher D. Zahm, Dustin A. Deming, Alyssa A. Leystra, Chelsie K. Sievers, Jamie N. Hadac, and Terrah J. Paul Olson

Abstract

PDF file - 28K, Differentially Expressed Gene Functional Categories between Adenomas and Intramucosal Carcinomas

Published
2023
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80. Body composition and lung cancer-associated cachexia in TRACERx

Author

Al-Sawaf, Othman, Weiss, Jakob, Skrzypski, Marcin, Lam, Jie Min, Karasaki, Takahiro, Zambrana, Francisco, Kidd, Andrew C, Frankell, Alexander M, Watkins, Thomas BK, Martinez-Ruiz, Carlos, Puttick, Clare, Black, James RM, Huebner, Ariana, Al Bakir, Maise, Sokac, Mateo, Collins, Susie, Veeriah, Selvaraju, Magno, Neil, Naceur-Lombardelli, Cristina, Prymas, Paulina, Toncheva, Antonia, Ward, Sophia, Jayanth, Nick, Salgado, Roberto, Bridge, Christopher P, Christiani, David C, Mak, Raymond H, Bay, Camden, Rosenthal, Michael, Sattar, Naveed, Welsh, Paul, Liu, Ying, Perrimon, Norbert, Popuri, Karteek, Beg, Mirza Faisal, McGranahan, Nicholas, Hackshaw, Allan, Breen, Danna M, O'Rahilly, Stephen, Birkbak, Nicolai J, Aerts, Hugo JWL, Jamal-Hanjani, Mariam, Swanton, Charles, Lester, Jason F, Bajaj, Amrita, Nakas, Apostolos, Sodha-Ramdeen, Azmina, Ang, Keng, Tufail, Mohamad, Chowdhry, Mohammed Fiyaz, Scotland, Molly, Boyles, Rebecca, Rathinam, Sridhar, Wilson, Claire, Marrone, Domenic, Dulloo, Sean, Fennell, Dean A, Matharu, Gurdeep, Shaw, Jacqui A, Riley, Joan, Primrose, Lindsay, Boleti, Ekaterini, Cheyne, Heather, Khalil, Mohammed, Richardson, Shirley, Cruickshank, Tracey, Price, Gillian, Kerr, Keith M, Benafif, Sarah, Gilbert, Kayleigh, Naidu, Babu, Patel, Akshay J, Osman, Aya, Lacson, Christer, Langman, Gerald, Shackleford, Helen, Djearaman, Madava, Kadiri, Salma, Middleton, Gary, Leek, Angela, Hodgkinson, Jack Davies, Totten, Nicola, Montero, Angeles, Smith, Elaine, Fontaine, Eustace, Granato, Felice, Doran, Helen, Novasio, Juliette, Rammohan, Kendadai, Joseph, Leena, Bishop, Paul, Shah, Rajesh, Moss, Stuart, Joshi, Vijay, Crosbie, Philip, Gomes, Fabio, Brown, Kate, Carter, Mathew, Chaturvedi, Anshuman, Priest, Lynsey, Oliveira, Pedro, Lindsay, Colin R, Blackhall, Fiona H, Krebs, Matthew G, Summers, Yvonne, Clipson, Alexandra, Tugwood, Jonathan, Kerr, Alastair, Rothwell, Dominic G, Kilgour, Elaine, Dive, Caroline, Schwarz, Roland F, Kaufmann, Tom L, Wilson, Gareth A, Rosenthal, Rachel, Van Loo, Peter, Szallasi, Zoltan, Kisistok, Judit, Diossy, Miklos, Demeulemeester, Jonas, Bunkum, Abigail, Stewart, Aengus, Magness, Alastair, Rowan, Andrew, Karamani, Angeliki, Chain, Benny, Campbell, Brittany B, Castignani, Carla, Bailey, Chris, Abbosh, Christopher, Weeden, Clare E, Lee, Claudia, Richard, Corentin, Hiley, Crispin T, Moore, David A, Pearce, David R, Karagianni, Despoina, Biswas, Dhruva, Levi, Dina, Hoxha, Elena, Cadieux, Elizabeth Larose, Lim, Emilia L, Colliver, Emma, Nye, Emma, Gronroos, Eva, Galvez-Cancino, Felip, Athanasopoulou, Foteini, Gimeno-Valiente, Francisco, Kassiotis, George, Stavrou, Georgia, Mastrokalos, Gerasimos, Zhai, Haoran, Lowe, Helen L, Matos, Ignacio Garcia, Goldman, Jacki, Reading, James L, Herrero, Javier, Rane, Jayant K, Nicod, Jerome, Hartley, John A, Peggs, Karl S, Enfield, Katey SS, Selvaraju, Kayalvizhi, Thol, Kerstin, Litchfield, Kevin, Ng, Kevin W, Chen, Kezhong, Dijkstra, Krijn, Grigoriadis, Kristiana, Thakkar, Krupa, Ensell, Leah, Shah, Mansi, Duran, Marcos Vasquez, Litovchenko, Maria, Sunderland, Mariana Werner, Hill, Mark S, Dietzen, Michelle, Leung, Michelle, Escudero, Mickael, Angelova, Mihaela, Tanic, Miljana, Sivakumar, Monica, Kanu, Nnennaya, Chervova, Olga, Lucas, Olivia, Pich, Oriol, Hobson, Philip, Pawlik, Piotr, Stone, Richard Kevin, Bentham, Robert, Hynds, Robert E, Vendramin, Roberto, Saghafinia, Sadegh, Lopez, Saioa, Gamble, Samuel, Ung, Seng Kuong Anakin, Quezada, Sergio A, Vanloo, Sharon, Zaccaria, Simone, Hessey, Sonya, Boeing, Stefan, Beck, Stephan, Bola, Supreet Kaur, Denner, Tamara, Marafioti, Teresa, Mourikis, Thanos P, Spanswick, Victoria, Barbe, Vittorio, Lu, Wei-Ting, Hill, William, Liu, Wing Kin, Wu, Yin, Naito, Yutaka, Ramsden, Zoe, Veiga, Catarina, Royle, Gary, Collins-Fekete, Charles-Antoine, Fraioli, Francesco, Ashford, Paul, Clark, Tristan, Forster, Martin D, Lee, Siow Ming, Borg, Elaine, Falzon, Mary, Papadatos-Pastos, Dionysis, Wilson, James, Ahmad, Tanya, Procter, Alexander James, Ahmed, Asia, Taylor, Magali N, Nair, Arjun, Lawrence, David, Patrini, Davide, Navani, Neal, Thakrar, Ricky M, Janes, Sam M, Hoogenboom, Emilie Martinoni, Monk, Fleur, Holding, James W, Choudhary, Junaid, Bhakhri, Kunal, Scarci, Marco, Hayward, Martin, Panagiotopoulos, Nikolaos, Gorman, Pat, Khiroya, Reena, Stephens, Robert CM, Wong, Yien Ning Sophia, Bandula, Steve, Sharp, Abigail, Smith, Sean, Gower, Nicole, Dhanda, Harjot Kaur, Chan, Kitty, Pilotti, Camilla, Leslie, Rachel, Grapa, Anca, Zhang, Hanyun, AbdulJabbar, Khalid, Pan, Xiaoxi, Yuan, Yinyin, Chuter, David, MacKenzie, Mairead, Chee, Serena, Alzetani, Aiman, Cave, Judith, Scarlett, Lydia, Richards, Jennifer, Ingram, Papawadee, Austin, Silvia, Lim, Eric, De Sousa, Paulo, Jordan, Simon, Rice, Alexandra, Raubenheimer, Hilgardt, Bhayani, Harshil, Ambrose, Lyn, Devaraj, Anand, Chavan, Hema, Begum, Sofina, Buderi, Silviu, Kaniu, Daniel, Malima, Mpho, Booth, Sarah, Nicholson, Andrew G, Fernandes, Nadia, Shah, Pratibha, Proli, Chiara, Hewish, Madeleine, Danson, Sarah, Shackcloth, Michael J, Robinson, Lily, Russell, Peter, Blyth, Kevin G, Dick, Craig, Le Quesne, John, Kirk, Alan, Asif, Mo, Bilancia, Rocco, Kostoulas, Nikos, and Thomas, Mathew

Subjects
Male, Proteomics, Cachexia, Lung Neoplasms, Antigens, Neoplasm, Carcinoma, Non-Small-Cell Lung, Body Weight, Body Composition, Humans, Neoplasm Recurrence, Local, Muscle, Skeletal, Neoplasm Proteins
Abstract

Cancer-associated cachexia (CAC) is a major contributor to morbidity and mortality in individuals with non-small cell lung cancer. Key features of CAC include alterations in body composition and body weight. Here, we explore the association between body composition and body weight with survival and delineate potential biological processes and mediators that contribute to the development of CAC. Computed tomography-based body composition analysis of 651 individuals in the TRACERx (TRAcking non-small cell lung Cancer Evolution through therapy (Rx)) study suggested that individuals in the bottom 20th percentile of the distribution of skeletal muscle or adipose tissue area at the time of lung cancer diagnosis, had significantly shorter lung cancer-specific survival and overall survival. This finding was validated in 420 individuals in the independent Boston Lung Cancer Study. Individuals classified as having developed CAC according to one or more features at relapse encompassing loss of adipose or muscle tissue, or body mass index-adjusted weight loss were found to have distinct tumor genomic and transcriptomic profiles compared with individuals who did not develop such features. Primary non-small cell lung cancers from individuals who developed CAC were characterized by enrichment of inflammatory signaling and epithelial-mesenchymal transitional pathways, and differentially expressed genes upregulated in these tumors included cancer-testis antigen MAGEA6 and matrix metalloproteinases, such as ADAMTS3. In an exploratory proteomic analysis of circulating putative mediators of cachexia performed in a subset of 110 individuals from TRACERx, a significant association between circulating GDF15 and loss of body weight, skeletal muscle and adipose tissue was identified at relapse, supporting the potential therapeutic relevance of targeting GDF15 in the management of CAC. ispartof: NATURE MEDICINE vol:29 issue:4 ispartof: location:United States status: Published online

Published
2023

81. The evolution of non-small cell lung cancer metastases in TRACERx

Author

Al Bakir, Maise, Huebner, Ariana, Martinez-Ruiz, Carlos, Grigoriadis, Kristiana, Watkins, Thomas BK, Pich, Oriol, Moore, David A, Veeriah, Selvaraju, Ward, Sophia, Laycock, Joanne, Johnson, Diana, Rowan, Andrew, Razaq, Maryam, Akther, Mita, Naceur-Lombardelli, Cristina, Prymas, Paulina, Toncheva, Antonia, Hessey, Sonya, Dietzen, Michelle, Colliver, Emma, Frankell, Alexander, Bunkum, Abigail, Lim, Emilia L, Karasaki, Takahiro, Abbosh, Christopher, Hiley, Crispin T, Hill, Mark S, Cook, Daniel E, Wilson, Gareth A, Salgado, Roberto, Nye, Emma, Stone, Richard Kevin, Fennell, Dean A, Price, Gillian, Kerr, Keith M, Naidu, Babu, Middleton, Gary, Summers, Yvonne, Lindsay, Colin R, Blackhall, Fiona H, Cave, Judith, Blyth, Kevin G, Nair, Arjun, Ahmed, Asia, Taylor, Magali N, Procter, Alexander James, Falzon, Mary, Lawrence, David, Navani, Neal, Thakrar, Ricky M, Janes, Sam M, Papadatos-Pastos, Dionysis, Forster, Martin D, Lee, Siow Ming, Ahmad, Tanya, Quezada, Sergio, Peggs, Karl S, Van Loo, Peter, Dive, Caroline, Hackshaw, Allan, Birkbak, Nicolai J, Zaccaria, Simone, Jamal-Hanjani, Mariam, McGranahan, Nicholas, Swanton, Charles, Lester, Jason F, Bajaj, Amrita, Nakas, Apostolos, Sodha-Ramdeen, Azmina, Ang, Keng, Tufail, Mohamad, Chowdhry, Mohammed Fiyaz, Scotland, Molly, Boyles, Rebecca, Rathinam, Sridhar, Wilson, Claire, Marrone, Domenic, Dulloo, Sean, Matharu, Gurdeep, Shaw, Jacqui A, Riley, Joan, Primrose, Lindsay, Boleti, Ekaterini, Cheyne, Heather, Khalil, Mohammed, Richardson, Shirley, Cruickshank, Tracey, Benafif, Sarah, Gilbert, Kayleigh, Patel, Akshay J, Osman, Aya, Lacson, Christer, Langman, Gerald, Shackleford, Helen, Djearaman, Madava, Kadiri, Salma, Leek, Angela, Hodgkinson, Jack Davies, Totten, Nicola, Montero, Angeles, Smith, Elaine, Fontaine, Eustace, Granato, Felice, Doran, Helen, Novasio, Juliette, Rammohan, Kendadai, Joseph, Leena, Bishop, Paul, Shah, Rajesh, Moss, Stuart, Joshi, Vijay, Crosbie, Philip, Gomes, Fabio, Brown, Kate, Carter, Mathew, Chaturvedi, Anshuman, Priest, Lynsey, Oliveira, Pedro, Krebs, Matthew G, Clipson, Alexandra, Tugwood, Jonathan, Kerr, Alastair, Rothwell, Dominic G, Kilgour, Elaine, Aerts, Hugo JWL, Schwarz, Roland F, Kaufmann, Tom L, Rosenthal, Rachel, Szallasi, Zoltan, Kisistok, Judit, Sokac, Mateo, Diossy, Miklos, Demeulemeester, Jonas, Stewart, Aengus, Magness, Alastair, Karamani, Angeliki, Chain, Benny, Campbell, Brittany B, Castignani, Carla, Bailey, Chris, Puttick, Clare, Weeden, Clare E, Lee, Claudia, Richard, Corentin, Pearce, David R, Karagianni, Despoina, Biswas, Dhruva, Levi, Dina, Hoxha, Elena, Larose Cadieux, Elizabeth, Gronroos, Eva, Galvez-Cancino, Felip, Athanasopoulou, Foteini, Gimeno-Valiente, Francisco, Kassiotis, George, Stavrou, Georgia, Mastrokalos, Gerasimos, Zhai, Haoran, Lowe, Helen L, Matos, Ignacio, Goldman, Jacki, Reading, James L, Black, James RM, Herrero, Javier, Rane, Jayant K, Nicod, Jerome, Lam, Jie Min, Hartley, John A, Enfield, Katey SS, Selvaraju, Kayalvizhi, Thol, Kerstin, Litchfield, Kevin, Ng, Kevin W, Chen, Kezhong, Dijkstra, Krijn, Thakkar, Krupa, Ensell, Leah, Shah, Mansi, Vasquez, Marcos, Litovchenko, Maria, Werner Sunderland, Mariana, Leung, Michelle, Escudero, Mickael, Angelova, Mihaela, Tanic, Miljana, Sivakumar, Monica, Kanu, Nnennaya, Chervova, Olga, Lucas, Olivia, Al-Sawaf, Othman, Hobson, Philip, Pawlik, Piotr, Bentham, Robert, Hynds, Robert E, Vendramin, Roberto, Saghafinia, Sadegh, Lopez, Saioa, Gamble, Samuel, Ung, Seng Kuong Anakin, Vanloo, Sharon, Boeing, Stefan, Beck, Stephan, Bola, Supreet Kaur, Denner, Tamara, Marafioti, Teresa, Mourikis, Thanos P, Spanswick, Victoria, Barbe, Vittorio, Lu, Wei-Ting, Hill, William, Liu, Wing Kin, Wu, Yin, Naito, Yutaka, Ramsden, Zoe, Veiga, Catarina, Royle, Gary, Collins-Fekete, Charles-Antoine, Fraioli, Francesco, Ashford, Paul, Clark, Tristan, Borg, Elaine, Wilson, James, Patrini, Davide, Martinoni Hoogenboom, Emilie, Monk, Fleur, Holding, James W, Choudhary, Junaid, Bhakhri, Kunal, Scarci, Marco, Hayward, Martin, Panagiotopoulos, Nikolaos, Gorman, Pat, Khiroya, Reena, Stephens, Robert CM, Wong, Yien Ning Sophia, Bandula, Steve, Sharp, Abigail, Smith, Sean, Gower, Nicole, Dhanda, Harjot Kaur, Chan, Kitty, Pilotti, Camilla, Leslie, Rachel, Grapa, Anca, Zhang, Hanyun, AbdulJabbar, Khalid, Pan, Xiaoxi, Yuan, Yinyin, Chuter, David, MacKenzie, Mairead, Chee, Serena, Alzetani, Aiman, Scarlett, Lydia, Richards, Jennifer, Ingram, Papawadee, Austin, Silvia, Lim, Eric, De Sousa, Paulo, Jordan, Simon, Rice, Alexandra, Raubenheimer, Hilgardt, Bhayani, Harshil, Ambrose, Lyn, Devaraj, Anand, Chavan, Hema, Begum, Sofina, Buderi, Silviu, Kaniu, Daniel, Malima, Mpho, Booth, Sarah, Nicholson, Andrew G, Fernandes, Nadia, Shah, Pratibha, Proli, Chiara, Hewish, Madeleine, Danson, Sarah, Shackcloth, Michael J, Robinson, Lily, Russell, Peter, Dick, Craig, Le Quesne, John, Kirk, Alan, Asif, Mo, Bilancia, Rocco, Kostoulas, Nikos, and Thomas, Mathew

Subjects
Clonal Evolution, Cohort Studies, Evolution, Molecular, Lung Neoplasms, Carcinoma, Non-Small-Cell Lung, Disease Progression, Humans, Neoplasm Metastasis, Neoplasm Recurrence, Local, Clone Cells
Abstract

Metastatic disease is responsible for the majority of cancer-related deaths1. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relapse. ispartof: NATURE vol:616 issue:7957 ispartof: location:England status: Published online

Published
2023

82. The evolution of lung cancer and impact of subclonal selection in TRACERx

Author

Frankell, Alexander M, Dietzen, Michelle, Al Bakir, Maise, Lim, Emilia L, Karasaki, Takahiro, Ward, Sophia, Veeriah, Selvaraju, Colliver, Emma, Huebner, Ariana, Bunkum, Abigail, Hill, Mark S, Grigoriadis, Kristiana, Moore, David A, Black, James RM, Liu, Wing Kin, Thol, Kerstin, Pich, Oriol, Watkins, Thomas BK, Naceur-Lombardelli, Cristina, Cook, Daniel E, Salgado, Roberto, Wilson, Gareth A, Bailey, Chris, Angelova, Mihaela, Bentham, Robert, Martinez-Ruiz, Carlos, Abbosh, Christopher, Nicholson, Andrew G, Le Quesne, John, Biswas, Dhruva, Rosenthal, Rachel, Puttick, Clare, Hessey, Sonya, Lee, Claudia, Prymas, Paulina, Toncheva, Antonia, Smith, Jon, Xing, Wei, Nicod, Jerome, Price, Gillian, Kerr, Keith M, Naidu, Babu, Middleton, Gary, Blyth, Kevin G, Fennell, Dean A, Forster, Martin D, Lee, Siow Ming, Falzon, Mary, Hewish, Madeleine, Shackcloth, Michael J, Lim, Eric, Benafif, Sarah, Russell, Peter, Boleti, Ekaterini, Krebs, Matthew G, Lester, Jason F, Papadatos-Pastos, Dionysis, Ahmad, Tanya, Thakrar, Ricky M, Lawrence, David, Navani, Neal, Janes, Sam M, Dive, Caroline, Blackhall, Fiona H, Summers, Yvonne, Cave, Judith, Marafioti, Teresa, Herrero, Javier, Quezada, Sergio A, Peggs, Karl S, Schwarz, Roland F, Van Loo, Peter, Miedema, Daniel M, Birkbak, Nicolai J, Hiley, Crispin T, Hackshaw, Allan, Zaccaria, Simone, Jamal-Hanjani, Mariam, McGranahan, Nicholas, Swanton, Charles, Bajaj, Amrita, Nakas, Apostolos, Sodha-Ramdeen, Azmina, Ang, Keng, Tufail, Mohamad, Chowdhry, Mohammed Fiyaz, Scotland, Molly, Boyles, Rebecca, Rathinam, Sridhar, Wilson, Claire, Marrone, Domenic, Dulloo, Sean, Matharu, Gurdeep, Shaw, Jacqui A, Riley, Joa, Primrose, Lindsay, Cheyne, Heather, Khalil, Mohammed, Richardson, Shirley, Cruickshank, Tracey, Gilbert, Kayleigh, Patel, Akshay J, Osman, Aya, Lacson, Christer, Langman, Gerald, Shackleford, Helen, Djearaman, Madava, Kadiri, Salma, Leek, Angela, Hodgkinson, Jack Davies, Totten, Nicola, Montero, Angeles, Smith, Elaine, Fontaine, Eustace, Granato, Felice, Doran, Helen, Novasio, Juliette, Rammohan, Kendadai, Joseph, Leena, Bishop, Paul, Shah, Rajesh, Moss, Stuart, Joshi, Vijay, Crosbie, Philip, Gomes, Fabio, Brown, Kate, Carter, Mathew, Chaturvedi, Anshuman, Priest, Lynsey, Oliveira, Pedro, Lindsay, Colin R, Clipson, Alexandra, Tugwood, Jonathan, Kerr, Alastair, Rothwell, Dominic G, Kilgour, Elaine, Aerts, Hugo JWL, Kaufmann, Tom L, Szallasi, Zoltan, Kisistok, Judit, Sokac, Mateo, Diossy, Miklos, Demeulemeester, Jonas, Stewart, Aengus, Magness, Alastair, Rowan, Andrew, Karamani, Angeliki, Chain, Benny, Campbell, Brittany B, Castignani, Carla, Weeden, Clare E, Richard, Corentin, Pearce, David R, Karagianni, Despoina, Levi, Dina, Hoxha, Elena, Larose Cadieux, Elizabeth, Nye, Emma, Gronroos, Eva, Galvez-Cancino, Felip, Athanasopoulou, Foteini, Gimeno-Valiente, Francisco, Kassiotis, George, Stavrou, Georgia, Mastrokalos, Gerasimos, Zhai, Haoran L, Lowe, Helen L, Matos, Ignacio, Goldman, Jacki, Reading, James L, Rane, Jayant K, Lam, Jie Min, Hartley, John A, Enfield, Katey SS, Selvaraju, Kayalvizhi, Litchfield, Kevin, Ng, Kevin W, Chen, Kezhong, Dijkstra, Krijn, Thakkar, Krupa, Ensell, Leah, Shah, Mansi, Vasquez, Marcos, Litovchenko, Maria, Werner Sunderland, Mariana, Leung, Michelle, Escudero, Mickael, Tanic, Miljana, Sivakumar, Monica, Kanu, Nnennaya, Chervova, Olga, Lucas, Olivia, Al-Sawaf, Othman, Hobson, Philip, Pawlik, Piotr, Stone, Richard Kevin, Hynds, Robert E, Vendramin, Roberto, Saghafinia, Sadegh, Lopez, Saioa, Gamble, Samuel, Ung, Seng Kuong Anakin, Vanloo, Sharon, Boeing, Stefan, Beck, Stephan, Bola, Supreet Kaur, Denner, Tamara, Mourikis, Thanos P, Spanswick, Victoria, Barbe, Vittorio, Lu, Wei-Ting, Hill, William, Wu, Yin, Naito, Yutaka, Ramsden, Zoe, Veiga, Catarina, Royle, Gary, Collins-Fekete, Charles-Antoine, Fraioli, Francesco, Ashford, Paul, Clark, Tristan, Borg, Elaine, Wilson, James, Procter, Alexander James, Ahmed, Asia, Taylor, Magali N, Nair, Arjun, Patrini, Davide, Martinoni Hoogenboom, Emilie, Monk, Fleur, Holding, James W, Choudhary, Junaid, Bhakhri, Kunal, Scarci, Marco, Hayward, Martin, Panagiotopoulos, Nikolaos, Gorman, Pat, Khiroya, Reena, Stephens, Robert CM, Wong, Yien Ning Sophia, Bandula, Steve, Sharp, Abigail, Smith, Sean, Gower, Nicole, Dhanda, Harjot Kaur, Chan, Kitty, Pilotti, Camilla, Leslie, Rachel, Grapa, Anca, Zhang, Hanyun, AbdulJabbar, Khalid, Pan, Xiaoxi, Yuan, Yinyin, Chuter, David, MacKenzie, Mairead, Chee, Serena, Alzetani, Aiman, Scarlett, Lydia, Richards, Jennifer, Ingram, Papawadee, Austin, Silvia, De Sousa, Paulo, Jordan, Simon, Rice, Alexandra, Raubenheimer, Hilgardt, Bhayani, Harshil, Ambrose, Lyn, Devaraj, Anand, Chavan, Hema, Begum, Sofina, Buderi, Silviu, Kaniu, Daniel, Malima, Mpho, Booth, Sarah, Fernandes, Nadia, Shah, Pratibha, Proli, Chiara, Danson, Sarah, Robinson, Lily, Dick, Craig, Kirk, Alan, Asif, Mo, Bilancia, Rocco, Kostoulas, Nikos, and Thomas, Mathew

Subjects
Lung Neoplasms, Treatment Outcome, DNA Copy Number Variations, Mutagenesis, Carcinoma, Non-Small-Cell Lung, Mutation, Smoking, Humans, Adenocarcinoma of Lung, Neoplasm Recurrence, Local, Phylogeny
Abstract

Lung cancer is the leading cause of cancer-associated mortality worldwide1. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource. ispartof: NATURE vol:616 issue:7957 ispartof: location:England status: Published online

Published
2023

83. Evolutionary characterization of lung adenocarcinoma morphology in TRACERx

Author

Karasaki, Takahiro, Moore, David A, Veeriah, Selvaraju, Naceur-Lombardelli, Cristina, Toncheva, Antonia, Magno, Neil, Ward, Sophia, Al Bakir, Maise, Watkins, Thomas BK, Grigoriadis, Kristiana, Huebner, Ariana, Hill, Mark S, Frankell, Alexander M, Abbosh, Christopher, Puttick, Clare, Zhai, Haoran, Gimeno-Valiente, Francisco, Saghafinia, Sadegh, Kanu, Nnennaya, Dietzen, Michelle, Pich, Oriol, Lim, Emilia L, Martinez-Ruiz, Carlos, Black, James RM, Biswas, Dhruva, Campbell, Brittany B, Lee, Claudia, Colliver, Emma, Enfield, Katey SS, Hessey, Sonya, Hiley, Crispin T, Zaccaria, Simone, Litchfield, Kevin, Birkbak, Nicolai J, Cadieux, Elizabeth Larose, Demeulemeester, Jonas, Van Loo, Peter, Adusumilli, Prasad R, Tan, Kay See, Cheema, Waseem, Sanchez-Vega, Francisco, Jones, David R, Rekhtman, Natasha, Travis, William D, Hackshaw, Allan, Marafioti, Teresa, Salgado, Roberto, Le Quesne, John, Nicholson, Andrew G, McGranahan, Nicholas, Swanton, Charles, Jamal-Hanjani, Mariam, Lester, Jason F, Bajaj, Amrita, Nakas, Apostolos, Sodha-Ramdeen, Azmina, Ang, Keng, Tufail, Mohamad, Chowdhry, Mohammed Fiyaz, Scotland, Molly, Boyles, Rebecca, Rathinam, Sridhar, Wilson, Claire, Marrone, Domenic, Dulloo, Sean, Fennell, Dean A, Matharu, Gurdeep, Shaw, Jacqui A, Riley, Joan, Primrose, Lindsay, Boleti, Ekaterini, Cheyne, Heather, Khalil, Mohammed, Richardson, Shirley, Cruickshank, Tracey, Price, Gillian, Kerr, Keith M, Benafif, Sarah, Gilbert, Kayleigh, Naidu, Babu, Patel, Akshay J, Osman, Aya, Lacson, Christer, Langman, Gerald, Shackleford, Helen, Djearaman, Madava, Kadiri, Salma, Middleton, Gary, Leek, Angela, Hodgkinson, Jack Davies, Totten, Nicola, Montero, Angeles, Smith, Elaine, Fontaine, Eustace, Granato, Felice, Doran, Helen, Novasio, Juliette, Rammohan, Kendadai, Joseph, Leena, Bishop, Paul, Shah, Rajesh, Moss, Stuart, Joshi, Vijay, Crosbie, Philip, Gomes, Fabio, Brown, Kate, Carter, Mathew, Chaturvedi, Anshuman, Priest, Lynsey, Oliveira, Pedro, Lindsay, Colin R, Blackhall, Fiona H, Krebs, Matthew G, Summers, Yvonne, Clipson, Alexandra, Tugwood, Jonathan, Kerr, Alastair, Rothwell, Dominic G, Kilgour, Elaine, Dive, Caroline, Aerts, Hugo JWL, Schwarz, Roland F, Kaufmann, Tom L, Wilson, Gareth A, Rosenthal, Rachel, Szallasi, Zoltan, Kisistok, Judit, Sokac, Mateo, Diossy, Miklos, Bunkum, Abigail, Stewart, Aengus, Magness, Alastair, Rowan, Andrew, Karamani, Angeliki, Chain, Benny, Castignani, Carla, Bailey, Chris, Weeden, Clare E, Richard, Corentin, Pearce, David R, Karagianni, Despoina, Levi, Dina, Hoxha, Elena, Nye, Emma, Gronroos, Eva, Galvez-Cancino, Felip, Athanasopoulou, Foteini, Kassiotis, George, Stavrou, Georgia, Mastrokalos, Gerasimos, Lowe, Helen L, Matos, Ignacio Garcia, Goldman, Jacki, Reading, James L, Herrero, Javier, Rane, Jayant K, Nicod, Jerome, Lam, Jie Min, Hartley, John A, Peggs, Karl S, Selvaraju, Kayalvizhi, Thol, Kerstin, Ng, Kevin W, Chen, Kezhong, Dijkstra, Krijn, Thakkar, Krupa, Ensell, Leah, Shah, Mansi, Duran, Marcos Vasquez, Litovchenko, Maria, Sunderland, Mariana Werner, Leung, Michelle, Escudero, Mickael, Angelova, Mihaela, Tanic, Miljana, Sivakumar, Monica, Chervova, Olga, Lucas, Olivia, Al-Sawaf, Othman, Prymas, Paulina, Hobson, Philip, Pawlik, Piotr, Stone, Richard Kevin, Bentham, Robert, Hynds, Robert E, Vendramin, Roberto, Lopez, Saioa, Gamble, Samuel, Ung, Seng Kuong Anakin, Quezada, Sergio A, Vanloo, Sharon, Boeing, Stefan, Beck, Stephan, Bola, Supreet Kaur, Denner, Tamara, Mourikis, Thanos P, Spanswick, Victoria, Barbe, Vittorio, Lu, Wei-Ting, Hill, William, Liu, Wing Kin, Wu, Yin, Naito, Yutaka, Ramsden, Zoe, Veiga, Catarina, Royle, Gary, Collins-Fekete, Charles-Antoine, Fraioli, Francesco, Ashford, Paul, Clark, Tristan, Forster, Martin D, Lee, Siow Ming, Borg, Elaine, Falzon, Mary, Papadatos-Pastos, Dionysis, Wilson, James, Ahmad, Tanya, Procter, Alexander James, Ahmed, Asia, Taylor, Magali N, Nair, Arjun, Lawrence, David, Patrini, Davide, Navani, Neal, Thakrar, Ricky M, Janes, Sam M, Hoogenboom, Emilie Martinoni, Monk, Fleur, Holding, James W, Choudhary, Junaid, Bhakhri, Kunal, Scarci, Marco, Hayward, Martin, Panagiotopoulos, Nikolaos, Gorman, Pat, Khiroya, Reena, Stephens, Robert CM, Wong, Yien Ning Sophia, Bandula, Steve, Sharp, Abigail, Smith, Sean, Gower, Nicole, Dhanda, Harjot Kaur, Chan, Kitty, Pilotti, Camilla, Leslie, Rachel, Grapa, Anca, Zhang, Hanyun, AbdulJabbar, Khalid, Pan, Xiaoxi, Yuan, Yinyin, Chuter, David, MacKenzie, Mairead, Chee, Serena, Alzetani, Aiman, Cave, Judith, Scarlett, Lydia, Richards, Jennifer, Ingram, Papawadee, Austin, Silvia, Lim, Eric, De Sousa, Paulo, Jordan, Simon, Rice, Alexandra, Raubenheimer, Hilgardt, Bhayani, Harshil, Ambrose, Lyn, Devaraj, Anand, Chavan, Hema, Begum, Sofina, Buderi, Silviu, Kaniu, Daniel, Malima, Mpho, Booth, Sarah, Fernandes, Nadia, Shah, Pratibha, Proli, Chiara, Hewish, Madeleine, Danson, Sarah, Shackcloth, Michael J, Robinson, Lily, Russell, Peter, Blyth, Kevin G, Dick, Craig, Kirk, Alan, Asif, Mo, Bilancia, Rocco, Kostoulas, Nikos, and Thomas, Mathew

Subjects
TRACERx Consortium
Abstract

Lung adenocarcinomas (LUADs) display a broad histological spectrum from low-grade lepidic tumors through to mid-grade acinar and papillary and high-grade solid, cribriform and micropapillary tumors. How morphology reflects tumor evolution and disease progression is poorly understood. Whole-exome sequencing data generated from 805 primary tumor regions and 121 paired metastatic samples across 248 LUADs from the TRACERx 421 cohort, together with RNA-sequencing data from 463 primary tumor regions, were integrated with detailed whole-tumor and regional histopathological analysis. Tumors with predominantly high-grade patterns showed increased chromosomal complexity, with higher burden of loss of heterozygosity and subclonal somatic copy number alterations. Individual regions in predominantly high-grade pattern tumors exhibited higher proliferation and lower clonal diversity, potentially reflecting large recent subclonal expansions. Co-occurrence of truncal loss of chromosomes 3p and 3q was enriched in predominantly low-/mid-grade tumors, while purely undifferentiated solid-pattern tumors had a higher frequency of truncal arm or focal 3q gains and SMARCA4 gene alterations compared with mixed-pattern tumors with a solid component, suggesting distinct evolutionary trajectories. Clonal evolution analysis revealed that tumors tend to evolve toward higher-grade patterns. The presence of micropapillary pattern and 'tumor spread through air spaces' were associated with intrathoracic recurrence, in contrast to the presence of solid/cribriform patterns, necrosis and preoperative circulating tumor DNA detection, which were associated with extra-thoracic recurrence. These data provide insights into the relationship between LUAD morphology, the underlying evolutionary genomic landscape, and clinical and anatomical relapse risk. ispartof: NATURE MEDICINE vol:29 issue:4 ispartof: location:United States status: Published online

Published
2023

84. Table S3 from Patient-Derived Cancer Organoid Cultures to Predict Sensitivity to Chemotherapy and Radiation

Author

Dustin A. Deming, Melissa C. Skala, Randall J. Kimple, Michael F. Bassetti, Irene M. Ong, Michael A. Newton, Kristina A. Matkowskyj, Kayla K. Lemmon, Mark E. Burkard, Evie H. Carchman, Devon Miller, Christine M. Walsh, Linda Clipson, Demetra P. Korkos, Susan N. Payne, Rosabella T. Pitera, Rebecca A. DeStefanis, Philip B. Emmerich, Carley M. Sprackling, Alyssa K. DeZeeuw, Kwangok P. Nickel, Mohammad Rezaul Karim, Joe T. Sharick, Amani A. Gillette, Christopher P. Babiarz, Alexander E. Yueh, Peter F. Favreau, and Cheri A. Pasch

Abstract

Detailed characteristics of CRC PDOCS.

Published
2023
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85. Figure S1 from Patient-Derived Cancer Organoid Cultures to Predict Sensitivity to Chemotherapy and Radiation

Author

Dustin A. Deming, Melissa C. Skala, Randall J. Kimple, Michael F. Bassetti, Irene M. Ong, Michael A. Newton, Kristina A. Matkowskyj, Kayla K. Lemmon, Mark E. Burkard, Evie H. Carchman, Devon Miller, Christine M. Walsh, Linda Clipson, Demetra P. Korkos, Susan N. Payne, Rosabella T. Pitera, Rebecca A. DeStefanis, Philip B. Emmerich, Carley M. Sprackling, Alyssa K. DeZeeuw, Kwangok P. Nickel, Mohammad Rezaul Karim, Joe T. Sharick, Amani A. Gillette, Christopher P. Babiarz, Alexander E. Yueh, Peter F. Favreau, and Cheri A. Pasch

Abstract

Dot plots corresponding to population distribution curves and graphs of individual replicates for bar graphs in Figure 4.

Published
2023
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86. Data from Patient-Derived Cancer Organoid Cultures to Predict Sensitivity to Chemotherapy and Radiation

Author

Dustin A. Deming, Melissa C. Skala, Randall J. Kimple, Michael F. Bassetti, Irene M. Ong, Michael A. Newton, Kristina A. Matkowskyj, Kayla K. Lemmon, Mark E. Burkard, Evie H. Carchman, Devon Miller, Christine M. Walsh, Linda Clipson, Demetra P. Korkos, Susan N. Payne, Rosabella T. Pitera, Rebecca A. DeStefanis, Philip B. Emmerich, Carley M. Sprackling, Alyssa K. DeZeeuw, Kwangok P. Nickel, Mohammad Rezaul Karim, Joe T. Sharick, Amani A. Gillette, Christopher P. Babiarz, Alexander E. Yueh, Peter F. Favreau, and Cheri A. Pasch

Abstract

Purpose:Cancer treatment is limited by inaccurate predictors of patient-specific therapeutic response. Therefore, some patients are exposed to unnecessary side effects and delays in starting effective therapy. A clinical tool that predicts treatment sensitivity for individual patients is needed.Experimental Design:Patient-derived cancer organoids were derived across multiple histologies. The histologic characteristics, mutation profile, clonal structure, and response to chemotherapy and radiation were assessed using bright-field and optical metabolic imaging on spheroid and single-cell levels, respectively.Results:We demonstrate that patient-derived cancer organoids represent the cancers from which they were derived, including key histologic and molecular features. These cultures were generated from numerous cancers, various biopsy sample types, and in different clinical settings. Next-generation sequencing reveals the presence of subclonal populations within the organoid cultures. These cultures allow for the detection of clonal heterogeneity with a greater sensitivity than bulk tumor sequencing. Optical metabolic imaging of these organoids provides cell-level quantification of treatment response and tumor heterogeneity allowing for resolution of therapeutic differences between patient samples. Using this technology, we prospectively predict treatment response for a patient with metastatic colorectal cancer.Conclusions:These studies add to the literature demonstrating feasibility to grow clinical patient-derived organotypic cultures for treatment effectiveness testing. Together, these culture methods and response assessment techniques hold great promise to predict treatment sensitivity for patients with cancer undergoing chemotherapy and/or radiation.

Published
2023
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87. Supplementary Data from Patient-Derived Cancer Organoid Cultures to Predict Sensitivity to Chemotherapy and Radiation

Author

Dustin A. Deming, Melissa C. Skala, Randall J. Kimple, Michael F. Bassetti, Irene M. Ong, Michael A. Newton, Kristina A. Matkowskyj, Kayla K. Lemmon, Mark E. Burkard, Evie H. Carchman, Devon Miller, Christine M. Walsh, Linda Clipson, Demetra P. Korkos, Susan N. Payne, Rosabella T. Pitera, Rebecca A. DeStefanis, Philip B. Emmerich, Carley M. Sprackling, Alyssa K. DeZeeuw, Kwangok P. Nickel, Mohammad Rezaul Karim, Joe T. Sharick, Amani A. Gillette, Christopher P. Babiarz, Alexander E. Yueh, Peter F. Favreau, and Cheri A. Pasch

Abstract

Supplementary Methods

Published
2023
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88. Data from Nucleolar Targeting of RelA(p65) Is Regulated by COMMD1-Dependent Ubiquitination

Author

Lesley A. Stark, Malcolm G. Dunlop, Karina Reinhardt, Alexandra Clipson, James Simpson, Carolyn J. Loveridge, and Hazel C. Thoms

Abstract

Stimulation of the NF-κB pathway can have proapoptotic or antiapoptotic consequences, and one mechanism that determines the outcome is the nuclear distribution of RelA. Certain stress stimuli induce nucleolar accumulation of RelA thereby mediating apoptosis, whereas others induce nucleoplasmic accumulation and inhibition of apoptosis. Here we investigated the mechanisms that regulate the nuclear distribution of RelA, specifically, the role of the ubiquitin/proteasome system. We found that stress-induced nucleolar translocation of RelA is preceded by ubiquitination of the protein. We also found that chemical proteasome inhibitors induce the ubiquitination and nucleolar translocation of RelA and that this is required for the apoptotic response to these agents. We show that the RelA nucleolar localization signal (amino acids 27–30) is a critical domain for ubiquitination of the protein but that the lysine residue within this motif is not a direct target. We show that RelA binds COMMD1, the rate-limiting component of the RelA ubiquitin ligase complex, in response to stress. Furthermore, we show that overexpression of COMMD1 promotes stress-mediated nucleolar targeting of RelA, whereas knockdown of COMMD1 blocks this effect, causing RelA to remain in the nucleoplasm. These data identify a new role for COMMD1 in regulating the nuclear/nucleolar distribution of RelA and suggest that ubiquitination acts as a signal for transport of RelA to the nucleolus. These findings have relevance to the design of chemopreventative/anticancer agents that act by targeting RelA to the nucleolar compartment. Cancer Res; 70(1); 139–49

Published
2023
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89. Supplementary Figures 1-7 from Mice Expressing Activated PI3K Rapidly Develop Advanced Colon Cancer

Author

Richard B. Halberg, Jamey P. Weichert, Jose R. Torrealba, Mary Kay Washington, Ruth Sullivan, Linda Clipson, Dawn M. Albrecht, Laura A. Nettekoven, Jamie N. Hadac, Terrah J. Paul Olson, Mohammed Farhoud, Christopher D. Zahm, Dustin A. Deming, and Alyssa A. Leystra

Abstract

PDF file - 583K, Mice expressing activated PI3K were scanned to identify those bearing tumors. After sacrifice, the intestine was removed to characterize tissue morphology, cell signaling and cell proliferation within the epithelium and the associated neoplasms

Published
2023
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90. Supplementary Movie from Mice Expressing Activated PI3K Rapidly Develop Advanced Colon Cancer

Author

Richard B. Halberg, Jamey P. Weichert, Jose R. Torrealba, Mary Kay Washington, Ruth Sullivan, Linda Clipson, Dawn M. Albrecht, Laura A. Nettekoven, Jamie N. Hadac, Terrah J. Paul Olson, Mohammed Farhoud, Christopher D. Zahm, Dustin A. Deming, and Alyssa A. Leystra

Abstract

WMP file - 834MB, The tumors in FC+ PIK3ca*+ mice exhibit high avidity for 124I-CLR1404. A mouse was injected with the imaging agent and then dual hybrid PET/CT colonography was performed. The agent was detected in all three tumors. This mouse is the same as shown in Figure 1, panels C and D. The agent was also detected in heart.

Published
2023
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95. Opportunistic Bacteria Dominate the Soil Microbiome Response to Phenanthrene in a Microcosm-Based Study

Author

Sean Storey, Mardiana Mohd Ashaari, Nicholas Clipson, Evelyn Doyle, and Alexandre B. de Menezes

Subjects
polycyclic aromatic hydrocarbons, microbiome, bioremediation, soil, phenanthrene, Microbiology, QR1-502
Abstract

Bioremediation offers a sustainable approach for removal of polycyclic aromatic hydrocarbons (PAHs) from the environment; however, information regarding the microbial communities involved remains limited. In this study, microbial community dynamics and the abundance of the key gene (PAH-RHDα) encoding a ring hydroxylating dioxygenase involved in PAH degradation were examined during degradation of phenanthrene in a podzolic soil from the site of a former timber treatment facility. The 10,000-fold greater abundance of this gene associated with Gram-positive bacteria found in phenanthrene-amended soil compared to unamended soil indicated the likely role of Gram-positive bacteria in PAH degradation. In contrast, the abundance of the Gram-negative PAHs-RHDα gene was very low throughout the experiment. While phenanthrene induced increases in the abundance of a small number of OTUs from the Actinomycetales and Sphingomonadale, most of the remainder of the community remained stable. A single unclassified OTU from the Micrococcaceae family increased ~20-fold in relative abundance, reaching 32% of the total sequences in amended microcosms on day 7 of the experiment. The relative abundance of this same OTU increased 4.5-fold in unamended soils, and a similar pattern was observed for the second most abundant PAH-responsive OTU, classified into the Sphingomonas genus. Furthermore, the relative abundance of both of these OTUs decreased substantially between days 7 and 17 in the phenanthrene-amended and control microcosms. This suggests that their opportunistic phenotype, in addition to likely PAH-degrading ability, was determinant in the vigorous growth of dominant PAH-responsive OTUs following phenanthrene amendment. This study provides new information on the temporal response of soil microbial communities to the presence and degradation of a significant environmental pollutant, and as such has the potential to inform the design of PAH bioremediation protocols.

Published
2018
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96. The conserved protective cyclic AMP-phosphodiesterase function PDE4B is expressed in the adenoma and adjacent normal colonic epithelium of mammals and silenced in colorectal cancer.

Author

Jennifer K Pleiman, Amy A Irving, Zhishi Wang, Erik Toraason, Linda Clipson, William F Dove, Dustin A Deming, and Michael A Newton

Subjects
Genetics, QH426-470
Abstract

Conservation over three mammalian genera-the mouse, rat, and human-has been found for a subset of the transcripts whose level differs between the adenoma and normal epithelium of the colon. Pde4b is one of the triply conserved transcripts whose level is enhanced both in the colonic adenoma and in the normal colonic epithelium, especially adjacent to adenomas. It encodes the phosphodiesterase PDE4B, specific for cAMP. Loss of PDE4B function in the ApcMin/+ mouse leads to a significant increase in the number of colonic adenomas. Similarly, Pde4b-deficient ApcMin/+ mice are hypersensitive to treatment by the inflammatory agent DSS, becoming moribund soon after treatment. These observations imply that the PDE4B function protects against ApcMin-induced adenomagenesis and inflammatory lethality. The paradoxical enhancement of the Pde4b transcript in the adenoma versus this inferred protective function of PDE4B can be rationalized by a feedback model in which PDE4B is first activated by early oncogenic stress involving cAMP and then, as reported for frank human colon cancer, inactivated by epigenetic silencing.

Published
2018
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99. The Social Networking Arena: Battle of the Sexes

Author

Clipson, Timothy W., Wilson, S. Ann, and DuFrene, Debbie D.

Abstract

Social networking via texting, Facebook, Twitter, and similar media is enormously popular with students, though it often leads to communication challenges along gender lines. Research supports the fact that men and women have divergent expectations for social networking and use it differently. Students can benefit from classroom experiences that raise their awareness of communication challenges associated with social networking and encourage them to assess their own areas for improvement.

Published
2012
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100. The utility of Apc-mutant rats in modeling human colon cancer

Author

Amy A. Irving, Kazuto Yoshimi, Marcia L. Hart, Taybor Parker, Linda Clipson, Madeline R. Ford, Takashi Kuramoto, William F. Dove, and James M. Amos-Landgraf

Subjects
APC, Allelic series, Animal models, Colorectal cancer, Medicine, Pathology, RB1-214
Abstract

Prior to the advent of genetic engineering in the mouse, the rat was the model of choice for investigating the etiology of cancer. Now, recent advances in the manipulation of the rat genome, combined with a growing recognition of the physiological differences between mice and rats, have reignited interest in the rat as a model of human cancer. Two recently developed rat models, the polyposis in the rat colon (Pirc) and Kyoto Apc Delta (KAD) strains, each carry mutations in the intestinal-cancer-associated adenomatous polyposis coli (Apc) gene. In contrast to mouse models carrying Apc mutations, in which cancers develop mainly in the small intestine rather than in the colon and there is no gender bias, these rat models exhibit colonic predisposition and gender-specific susceptibility, as seen in human colon cancer. The rat also provides other experimental resources as a model organism that are not provided by the mouse: the structure of its chromosomes facilitates the analysis of genomic events, the size of its colon permits longitudinal analysis of tumor growth, and the size of biological samples from the animal facilitates multiplexed molecular analyses of the tumor and its host. Thus, the underlying biology and experimental resources of these rat models provide important avenues for investigation. We anticipate that advances in disease modeling in the rat will synergize with resources that are being developed in the mouse to provide a deeper understanding of human colon cancer.

Published
2014
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