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346 results on '"Brown, Kevin R."'

1. The TSC22D, WNK, and NRBP gene families exhibit functional buffering and evolved with Metazoa for cell volume regulation

Author

Xiao, Yu-Xi, Lee, Seon Yong, Aguilera-Uribe, Magali, Samson, Reuben, Au, Aaron, Khanna, Yukti, Liu, Zetao, Cheng, Ran, Aulakh, Kamaldeep, Wei, Jiarun, Farias, Adrian Granda, Reilly, Taylor, Birkadze, Saba, Habsid, Andrea, Brown, Kevin R., Chan, Katherine, Mero, Patricia, Huang, Jie Qi, Billmann, Maximilian, Rahman, Mahfuzur, Myers, Chad, Andrews, Brenda J., Youn, Ji-Young, Yip, Christopher M., Rotin, Daniela, Derry, W. Brent, Forman-Kay, Julie D., Moses, Alan M., Pritišanac, Iva, Gingras, Anne-Claude, and Moffat, Jason

Published
2024
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2. NOX4 links metabolic regulation in pancreatic cancer to endoplasmic reticulum redox vulnerability and dependence on PRDX4

Author

Jain, Pallavi, Dvorkin-Gheva, Anna, Mollen, Erik, Malbeteau, Lucie, Xie, Michael, Jessa, Fatima, Dhavarasa, Piriththiv, Chung, Stephen, Brown, Kevin R, Jang, Gun Ho, Vora, Parth, Notta, Faiyaz, Moffat, Jason, Hedley, David, Boutros, Paul C, Wouters, Bradly G, and Koritzinsky, Marianne

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Digestive Diseases, Pancreatic Cancer, Rare Diseases, Cancer, Genetics, 2.1 Biological and endogenous factors, Aetiology, Endoplasmic Reticulum, Humans, Hydrogen Peroxide, NADP, NADPH Oxidase 4, Oxidation-Reduction, Pancreatic Neoplasms, Peroxiredoxins, Reactive Oxygen Species
Abstract

There is an urgent need to identify vulnerabilities in pancreatic ductal adenocarcinoma (PDAC). PDAC cells acquire metabolic changes that augment NADPH production and cytosolic redox homeostasis. Here, we show that high NADPH levels drive activity of NADPH oxidase 4 (NOX4) expressed in the endoplasmic reticulum (ER) membrane. NOX4 produces H2O2 metabolized by peroxiredoxin 4 (PRDX4) in the ER lumen. Using functional genomics and subsequent in vitro and in vivo validations, we find that PDAC cell lines with high NADPH levels are dependent on PRDX4 for their growth and survival. PRDX4 addiction is associated with increased reactive oxygen species, a DNA-PKcs-governed DNA damage response and radiosensitivity, which can be rescued by depletion of NOX4 or NADPH. Hence, this study has identified NOX4 as a protein that paradoxically converts the reducing power of the cytosol to an ER-specific oxidative stress vulnerability in PDAC that may be therapeutically exploited by targeting PRDX4.

Published
2021

3. Survival-based CRISPR genetic screens across a panel of permissive cell lines identify common and cell-specific SARS-CoV-2 host factors

Author

Chan, Katherine, Farias, Adrian Granda, Lee, Hunsang, Guvenc, Furkan, Mero, Patricia, Brown, Kevin R., Ward, Henry, Billmann, Maximilian, Aulakh, Kamaldeep, Astori, Audrey, Haider, Shahan, Marcon, Edyta, Braunschweig, Ulrich, Pu, Shuye, Habsid, Andrea, Yan Tong, Amy Hin, Christie-Holmes, Natasha, Budylowski, Patrick, Ghalami, Ayoob, Mubareka, Samira, Maguire, Finlay, Banerjee, Arinjay, Mossman, Karen L., Greenblatt, Jack, Gray-Owen, Scott D., Raught, Brian, Blencowe, Benjamin J., Taipale, Mikko, Myers, Chad, and Moffat, Jason

Published
2023
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4. Cancer-selective metabolic vulnerabilities in MYC-amplified medulloblastoma

Author

Gwynne, William D., Suk, Yujin, Custers, Stefan, Mikolajewicz, Nicholas, Chan, Jeremy K., Zador, Zsolt, Chafe, Shawn C., Zhai, Kui, Escudero, Laura, Zhang, Cunjie, Zaslaver, Olga, Chokshi, Chirayu, Shaikh, Muhammad Vaseem, Bakhshinyan, David, Burns, Ian, Chaudhry, Iqra, Nachmani, Omri, Mobilio, Daniel, Maich, William T., Mero, Patricia, Brown, Kevin R., Quaile, Andrew T., Venugopal, Chitra, Moffat, Jason, Montenegro-Burke, J. Rafael, and Singh, Sheila K.

Published
2022
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7. TSC22D, WNK and NRBP gene families exhibit functional buffering and evolved with Metazoa for macromolecular crowd sensing

Author

Xiao, Yu-Xi, primary, Lee, Seon Yong, additional, Aguilera-Uribe, Magali, additional, Samson, Reuben, additional, Au, Aaron, additional, Khanna, Yukti, additional, Liu, Zetao, additional, Cheng, Ran, additional, Aulakh, Kamaldeep, additional, Wei, Jiarun, additional, Farias, Adrian Granda, additional, Reilly, Taylor, additional, Habsid, Andrea, additional, Brown, Kevin R., additional, Chan, Katherine, additional, Mero, Patricia, additional, Huang, Jie Qi, additional, Billmann, Maximilian, additional, Rahman, Mahfuzur, additional, Myers, Chad, additional, Andrews, Brenda J., additional, Youn, Ji-Young, additional, Yip, Christopher M., additional, Rotin, Daniela, additional, Derry, W. Brent, additional, Forman-Kay, Julie D., additional, Moses, Alan M., additional, Pritišanac, Iva, additional, Gingras, Anne-Claude, additional, and Moffat, Jason, additional

Published
2024
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8. Functional genomic landscape of cancer-intrinsic evasion of killing by T cells

Author

Lawson, Keith A., Sousa, Cristovão M., Zhang, Xiaoyu, Kim, Eiru, Akthar, Rummy, Caumanns, Joseph J., Yao, Yuxi, Mikolajewicz, Nicholas, Ross, Catherine, Brown, Kevin R., Zid, Abdelrahman Abou, Fan, Zi Peng, Hui, Shirley, Krall, Jordan A., Simons, Donald M., Slater, Chloe J., De Jesus, Victor, Tang, Lujia, Singh, Richa, Goldford, Joshua E., Martin, Sarah, Huang, Qian, Francis, Elizabeth A., Habsid, Andrea, Climie, Ryan, Tieu, David, Wei, Jiarun, Li, Ren, Tong, Amy Hin Yan, Aregger, Michael, Chan, Katherine S., Han, Hong, Wang, Xiaowei, Mero, Patricia, Brumell, John H., Finelli, Antonio, Ailles, Laurie, Bader, Gary, Smolen, Gromoslaw A., Kingsbury, Gillian A., Hart, Traver, Kung, Charles, and Moffat, Jason

Published
2020
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10. Systematic mapping of genetic interactions for de novo fatty acid synthesis identifies C12orf49 as a regulator of lipid metabolism

Author

Aregger, Michael, Lawson, Keith A., Billmann, Maximillian, Costanzo, Michael, Tong, Amy H. Y., Chan, Katherine, Rahman, Mahfuzur, Brown, Kevin R., Ross, Catherine, Usaj, Matej, Nedyalkova, Lucy, Sizova, Olga, Habsid, Andrea, Pawling, Judy, Lin, Zhen-Yuan, Abdouni, Hala, Wong, Cassandra J., Weiss, Alexander, Mero, Patricia, Dennis, James W., Gingras, Anne-Claude, Myers, Chad L., Andrews, Brenda J., Boone, Charles, and Moffat, Jason

Published
2020
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12. Bmi1 regulates human glioblastoma stem cells through activation of differential gene networks in CD133+ brain tumor initiating cells

Author

Vora, Parvez, Seyfrid, Mathieu, Venugopal, Chitra, Qazi, Maleeha A., Salim, Sabra, Isserlin, Ruth, Subapanditha, Minomi, O’Farrell, Erin, Mahendram, Sujeivan, Singh, Mohini, Bakhshinyan, David, Chokshi, Chirayu, McFarlane, Nicole, Dvorkin-Gheva, Anna, Brown, Kevin R., Murty, Naresh, Moffat, Jason, Bader, Gary D., and Singh, Sheila K.

Published
2019
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13. High-Throughput Mapping of a Dynamic Signaling Network in Mammalian Cells

Author

Barrios-Rodiles, Miriam, Brown, Kevin R., Ozdamar, Barish, Bose, Rohit, Liu, Zhong, Donovan, Robert S., Shinjo, Fukiko, Liu, Yongmei, Dembowy, Joanna, Taylor, Ian W., Luga, Valbona, Przulj, Natasa, Robinson, Mark, Suzuki, Harukazu, Hayashizaki, Yoshihide, Jurisica, Igor, and Wrana, Jeffrey L.

Published
2005

14. Supplementary Figure from Ontogeny and Vulnerabilities of Drug-Tolerant Persisters in HER2+ Breast Cancer

Author

Chang, Chewei Anderson, primary, Jen, Jayu, primary, Jiang, Shaowen, primary, Sayad, Azin, primary, Mer, Arvind Singh, primary, Brown, Kevin R., primary, Nixon, Allison M.L., primary, Dhabaria, Avantika, primary, Tang, Kwan Ho, primary, Venet, David, primary, Sotiriou, Christos, primary, Deng, Jiehui, primary, Wong, Kwok-kin, primary, Adams, Sylvia, primary, Meyn, Peter, primary, Heguy, Adriana, primary, Skok, Jane A., primary, Tsirigos, Aristotelis, primary, Ueberheide, Beatrix, primary, Moffat, Jason, primary, Singh, Abhyudai, primary, Haibe-Kains, Benjamin, primary, Khodadadi-Jamayran, Alireza, primary, and Neel, Benjamin G., primary

Published
2023
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15. Data from Ontogeny and Vulnerabilities of Drug-Tolerant Persisters in HER2+ Breast Cancer

Author

Chang, Chewei Anderson, primary, Jen, Jayu, primary, Jiang, Shaowen, primary, Sayad, Azin, primary, Mer, Arvind Singh, primary, Brown, Kevin R., primary, Nixon, Allison M.L., primary, Dhabaria, Avantika, primary, Tang, Kwan Ho, primary, Venet, David, primary, Sotiriou, Christos, primary, Deng, Jiehui, primary, Wong, Kwok-kin, primary, Adams, Sylvia, primary, Meyn, Peter, primary, Heguy, Adriana, primary, Skok, Jane A., primary, Tsirigos, Aristotelis, primary, Ueberheide, Beatrix, primary, Moffat, Jason, primary, Singh, Abhyudai, primary, Haibe-Kains, Benjamin, primary, Khodadadi-Jamayran, Alireza, primary, and Neel, Benjamin G., primary

Published
2023
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16. Supplementary Table from Ontogeny and Vulnerabilities of Drug-Tolerant Persisters in HER2+ Breast Cancer

Author

Chang, Chewei Anderson, primary, Jen, Jayu, primary, Jiang, Shaowen, primary, Sayad, Azin, primary, Mer, Arvind Singh, primary, Brown, Kevin R., primary, Nixon, Allison M.L., primary, Dhabaria, Avantika, primary, Tang, Kwan Ho, primary, Venet, David, primary, Sotiriou, Christos, primary, Deng, Jiehui, primary, Wong, Kwok-kin, primary, Adams, Sylvia, primary, Meyn, Peter, primary, Heguy, Adriana, primary, Skok, Jane A., primary, Tsirigos, Aristotelis, primary, Ueberheide, Beatrix, primary, Moffat, Jason, primary, Singh, Abhyudai, primary, Haibe-Kains, Benjamin, primary, Khodadadi-Jamayran, Alireza, primary, and Neel, Benjamin G., primary

Published
2023
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17. Supplementary Table 5a from Essential Gene Profiles in Breast, Pancreatic, and Ovarian Cancer Cells

Author

Marcotte, Richard, primary, Brown, Kevin R., primary, Suarez, Fernando, primary, Sayad, Azin, primary, Karamboulas, Konstantina, primary, Krzyzanowski, Paul M., primary, Sircoulomb, Fabrice, primary, Medrano, Mauricio, primary, Fedyshyn, Yaroslav, primary, Koh, Judice L.Y., primary, van Dyk, Dewald, primary, Fedyshyn, Bohdana, primary, Luhova, Marianna, primary, Brito, Glauber C., primary, Vizeacoumar, Franco J., primary, Vizeacoumar, Frederick S., primary, Datti, Alessandro, primary, Kasimer, Dahlia, primary, Buzina, Alla, primary, Mero, Patricia, primary, Misquitta, Christine, primary, Normand, Josee, primary, Haider, Maliha, primary, Ketela, Troy, primary, Wrana, Jeffrey L., primary, Rottapel, Robert, primary, Neel, Benjamin G., primary, and Moffat, Jason, primary

Published
2023
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18. Supplementary Figures 1-8 from Essential Gene Profiles in Breast, Pancreatic, and Ovarian Cancer Cells

Author

Marcotte, Richard, primary, Brown, Kevin R., primary, Suarez, Fernando, primary, Sayad, Azin, primary, Karamboulas, Konstantina, primary, Krzyzanowski, Paul M., primary, Sircoulomb, Fabrice, primary, Medrano, Mauricio, primary, Fedyshyn, Yaroslav, primary, Koh, Judice L.Y., primary, van Dyk, Dewald, primary, Fedyshyn, Bohdana, primary, Luhova, Marianna, primary, Brito, Glauber C., primary, Vizeacoumar, Franco J., primary, Vizeacoumar, Frederick S., primary, Datti, Alessandro, primary, Kasimer, Dahlia, primary, Buzina, Alla, primary, Mero, Patricia, primary, Misquitta, Christine, primary, Normand, Josee, primary, Haider, Maliha, primary, Ketela, Troy, primary, Wrana, Jeffrey L., primary, Rottapel, Robert, primary, Neel, Benjamin G., primary, and Moffat, Jason, primary

Published
2023
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19. Supplementary Table 2 from Essential Gene Profiles in Breast, Pancreatic, and Ovarian Cancer Cells

Author

Marcotte, Richard, primary, Brown, Kevin R., primary, Suarez, Fernando, primary, Sayad, Azin, primary, Karamboulas, Konstantina, primary, Krzyzanowski, Paul M., primary, Sircoulomb, Fabrice, primary, Medrano, Mauricio, primary, Fedyshyn, Yaroslav, primary, Koh, Judice L.Y., primary, van Dyk, Dewald, primary, Fedyshyn, Bohdana, primary, Luhova, Marianna, primary, Brito, Glauber C., primary, Vizeacoumar, Franco J., primary, Vizeacoumar, Frederick S., primary, Datti, Alessandro, primary, Kasimer, Dahlia, primary, Buzina, Alla, primary, Mero, Patricia, primary, Misquitta, Christine, primary, Normand, Josee, primary, Haider, Maliha, primary, Ketela, Troy, primary, Wrana, Jeffrey L., primary, Rottapel, Robert, primary, Neel, Benjamin G., primary, and Moffat, Jason, primary

Published
2023
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20. Supplementary Table 1 from Essential Gene Profiles in Breast, Pancreatic, and Ovarian Cancer Cells

Author

Marcotte, Richard, primary, Brown, Kevin R., primary, Suarez, Fernando, primary, Sayad, Azin, primary, Karamboulas, Konstantina, primary, Krzyzanowski, Paul M., primary, Sircoulomb, Fabrice, primary, Medrano, Mauricio, primary, Fedyshyn, Yaroslav, primary, Koh, Judice L.Y., primary, van Dyk, Dewald, primary, Fedyshyn, Bohdana, primary, Luhova, Marianna, primary, Brito, Glauber C., primary, Vizeacoumar, Franco J., primary, Vizeacoumar, Frederick S., primary, Datti, Alessandro, primary, Kasimer, Dahlia, primary, Buzina, Alla, primary, Mero, Patricia, primary, Misquitta, Christine, primary, Normand, Josee, primary, Haider, Maliha, primary, Ketela, Troy, primary, Wrana, Jeffrey L., primary, Rottapel, Robert, primary, Neel, Benjamin G., primary, and Moffat, Jason, primary

Published
2023
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21. Supplementary Table 6 from Essential Gene Profiles in Breast, Pancreatic, and Ovarian Cancer Cells

Author

Marcotte, Richard, primary, Brown, Kevin R., primary, Suarez, Fernando, primary, Sayad, Azin, primary, Karamboulas, Konstantina, primary, Krzyzanowski, Paul M., primary, Sircoulomb, Fabrice, primary, Medrano, Mauricio, primary, Fedyshyn, Yaroslav, primary, Koh, Judice L.Y., primary, van Dyk, Dewald, primary, Fedyshyn, Bohdana, primary, Luhova, Marianna, primary, Brito, Glauber C., primary, Vizeacoumar, Franco J., primary, Vizeacoumar, Frederick S., primary, Datti, Alessandro, primary, Kasimer, Dahlia, primary, Buzina, Alla, primary, Mero, Patricia, primary, Misquitta, Christine, primary, Normand, Josee, primary, Haider, Maliha, primary, Ketela, Troy, primary, Wrana, Jeffrey L., primary, Rottapel, Robert, primary, Neel, Benjamin G., primary, and Moffat, Jason, primary

Published
2023
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22. Supplementary Table 3 from Essential Gene Profiles in Breast, Pancreatic, and Ovarian Cancer Cells

Author

Marcotte, Richard, primary, Brown, Kevin R., primary, Suarez, Fernando, primary, Sayad, Azin, primary, Karamboulas, Konstantina, primary, Krzyzanowski, Paul M., primary, Sircoulomb, Fabrice, primary, Medrano, Mauricio, primary, Fedyshyn, Yaroslav, primary, Koh, Judice L.Y., primary, van Dyk, Dewald, primary, Fedyshyn, Bohdana, primary, Luhova, Marianna, primary, Brito, Glauber C., primary, Vizeacoumar, Franco J., primary, Vizeacoumar, Frederick S., primary, Datti, Alessandro, primary, Kasimer, Dahlia, primary, Buzina, Alla, primary, Mero, Patricia, primary, Misquitta, Christine, primary, Normand, Josee, primary, Haider, Maliha, primary, Ketela, Troy, primary, Wrana, Jeffrey L., primary, Rottapel, Robert, primary, Neel, Benjamin G., primary, and Moffat, Jason, primary

Published
2023
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23. Supplementary Methods from Essential Gene Profiles in Breast, Pancreatic, and Ovarian Cancer Cells

Author

Marcotte, Richard, primary, Brown, Kevin R., primary, Suarez, Fernando, primary, Sayad, Azin, primary, Karamboulas, Konstantina, primary, Krzyzanowski, Paul M., primary, Sircoulomb, Fabrice, primary, Medrano, Mauricio, primary, Fedyshyn, Yaroslav, primary, Koh, Judice L.Y., primary, van Dyk, Dewald, primary, Fedyshyn, Bohdana, primary, Luhova, Marianna, primary, Brito, Glauber C., primary, Vizeacoumar, Franco J., primary, Vizeacoumar, Frederick S., primary, Datti, Alessandro, primary, Kasimer, Dahlia, primary, Buzina, Alla, primary, Mero, Patricia, primary, Misquitta, Christine, primary, Normand, Josee, primary, Haider, Maliha, primary, Ketela, Troy, primary, Wrana, Jeffrey L., primary, Rottapel, Robert, primary, Neel, Benjamin G., primary, and Moffat, Jason, primary

Published
2023
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24. Supplementary Table 7 from Essential Gene Profiles in Breast, Pancreatic, and Ovarian Cancer Cells

Author

Marcotte, Richard, primary, Brown, Kevin R., primary, Suarez, Fernando, primary, Sayad, Azin, primary, Karamboulas, Konstantina, primary, Krzyzanowski, Paul M., primary, Sircoulomb, Fabrice, primary, Medrano, Mauricio, primary, Fedyshyn, Yaroslav, primary, Koh, Judice L.Y., primary, van Dyk, Dewald, primary, Fedyshyn, Bohdana, primary, Luhova, Marianna, primary, Brito, Glauber C., primary, Vizeacoumar, Franco J., primary, Vizeacoumar, Frederick S., primary, Datti, Alessandro, primary, Kasimer, Dahlia, primary, Buzina, Alla, primary, Mero, Patricia, primary, Misquitta, Christine, primary, Normand, Josee, primary, Haider, Maliha, primary, Ketela, Troy, primary, Wrana, Jeffrey L., primary, Rottapel, Robert, primary, Neel, Benjamin G., primary, and Moffat, Jason, primary

Published
2023
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25. Data from Essential Gene Profiles in Breast, Pancreatic, and Ovarian Cancer Cells

Author

Marcotte, Richard, primary, Brown, Kevin R., primary, Suarez, Fernando, primary, Sayad, Azin, primary, Karamboulas, Konstantina, primary, Krzyzanowski, Paul M., primary, Sircoulomb, Fabrice, primary, Medrano, Mauricio, primary, Fedyshyn, Yaroslav, primary, Koh, Judice L.Y., primary, van Dyk, Dewald, primary, Fedyshyn, Bohdana, primary, Luhova, Marianna, primary, Brito, Glauber C., primary, Vizeacoumar, Franco J., primary, Vizeacoumar, Frederick S., primary, Datti, Alessandro, primary, Kasimer, Dahlia, primary, Buzina, Alla, primary, Mero, Patricia, primary, Misquitta, Christine, primary, Normand, Josee, primary, Haider, Maliha, primary, Ketela, Troy, primary, Wrana, Jeffrey L., primary, Rottapel, Robert, primary, Neel, Benjamin G., primary, and Moffat, Jason, primary

Published
2023
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26. Supplementary Table 8 from Essential Gene Profiles in Breast, Pancreatic, and Ovarian Cancer Cells

Author

Marcotte, Richard, primary, Brown, Kevin R., primary, Suarez, Fernando, primary, Sayad, Azin, primary, Karamboulas, Konstantina, primary, Krzyzanowski, Paul M., primary, Sircoulomb, Fabrice, primary, Medrano, Mauricio, primary, Fedyshyn, Yaroslav, primary, Koh, Judice L.Y., primary, van Dyk, Dewald, primary, Fedyshyn, Bohdana, primary, Luhova, Marianna, primary, Brito, Glauber C., primary, Vizeacoumar, Franco J., primary, Vizeacoumar, Frederick S., primary, Datti, Alessandro, primary, Kasimer, Dahlia, primary, Buzina, Alla, primary, Mero, Patricia, primary, Misquitta, Christine, primary, Normand, Josee, primary, Haider, Maliha, primary, Ketela, Troy, primary, Wrana, Jeffrey L., primary, Rottapel, Robert, primary, Neel, Benjamin G., primary, and Moffat, Jason, primary

Published
2023
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27. Supplementary Table 9 from Essential Gene Profiles in Breast, Pancreatic, and Ovarian Cancer Cells

Author

Marcotte, Richard, primary, Brown, Kevin R., primary, Suarez, Fernando, primary, Sayad, Azin, primary, Karamboulas, Konstantina, primary, Krzyzanowski, Paul M., primary, Sircoulomb, Fabrice, primary, Medrano, Mauricio, primary, Fedyshyn, Yaroslav, primary, Koh, Judice L.Y., primary, van Dyk, Dewald, primary, Fedyshyn, Bohdana, primary, Luhova, Marianna, primary, Brito, Glauber C., primary, Vizeacoumar, Franco J., primary, Vizeacoumar, Frederick S., primary, Datti, Alessandro, primary, Kasimer, Dahlia, primary, Buzina, Alla, primary, Mero, Patricia, primary, Misquitta, Christine, primary, Normand, Josee, primary, Haider, Maliha, primary, Ketela, Troy, primary, Wrana, Jeffrey L., primary, Rottapel, Robert, primary, Neel, Benjamin G., primary, and Moffat, Jason, primary

Published
2023
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28. Supplementary Table 4 from Essential Gene Profiles in Breast, Pancreatic, and Ovarian Cancer Cells

Author

Marcotte, Richard, primary, Brown, Kevin R., primary, Suarez, Fernando, primary, Sayad, Azin, primary, Karamboulas, Konstantina, primary, Krzyzanowski, Paul M., primary, Sircoulomb, Fabrice, primary, Medrano, Mauricio, primary, Fedyshyn, Yaroslav, primary, Koh, Judice L.Y., primary, van Dyk, Dewald, primary, Fedyshyn, Bohdana, primary, Luhova, Marianna, primary, Brito, Glauber C., primary, Vizeacoumar, Franco J., primary, Vizeacoumar, Frederick S., primary, Datti, Alessandro, primary, Kasimer, Dahlia, primary, Buzina, Alla, primary, Mero, Patricia, primary, Misquitta, Christine, primary, Normand, Josee, primary, Haider, Maliha, primary, Ketela, Troy, primary, Wrana, Jeffrey L., primary, Rottapel, Robert, primary, Neel, Benjamin G., primary, and Moffat, Jason, primary

Published
2023
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29. Targeting axonal guidance dependencies in glioblastoma with ROBO1 CAR T cells

Author

Chokshi, Chirayu R., Shaikh, Muhammad Vaseem, Brakel, Benjamin, Rossotti, Martin A., Tieu, David, Maich, William, Anand, Alisha, Chafe, Shawn C., Zhai, Kui, Suk, Yujin, Kieliszek, Agata M., Miletic, Petar, Mikolajewicz, Nicholas, Chen, David, McNicol, Jamie D., Chan, Katherine, Tong, Amy H. Y., Kuhlmann, Laura, Liu, Lina, Alizada, Zahra, Mobilio, Daniel, Tatari, Nazanin, Savage, Neil, Aghaei, Nikoo, Grewal, Shan, Puri, Anish, Subapanditha, Minomi, McKenna, Dillon, Ignatchenko, Vladimir, Salamoun, Joseph M., Kwiecien, Jacek M., Wipf, Peter, Sharlow, Elizabeth R., Provias, John P., Lu, Jian-Qiang, Lazo, John S., Kislinger, Thomas, Lu, Yu, Brown, Kevin R., Venugopal, Chitra, Henry, Kevin A., Moffat, Jason, and Singh, Sheila K.

Abstract

Resistance to genotoxic therapies and tumor recurrence are hallmarks of glioblastoma (GBM), an aggressive brain tumor. In this study, we investigated functional drivers of post-treatment recurrent GBM through integrative genomic analyses, genome-wide genetic perturbation screens in patient-derived GBM models and independent lines of validation. Specific genetic dependencies were found consistent across recurrent tumor models, accompanied by increased mutational burden and differential transcript and protein expression compared to its primary GBM predecessor. Our observations suggest a multi-layered genetic response to drive tumor recurrence and implicate PTP4A2(protein tyrosine phosphatase 4A2) as a modulator of self-renewal, proliferation and tumorigenicity in recurrent GBM. Genetic perturbation or small-molecule inhibition of PTP4A2 acts through a dephosphorylation axis with roundabout guidance receptor 1 (ROBO1) and its downstream molecular players, exploiting a functional dependency on ROBO signaling. Because a pan-PTP4A inhibitor was limited by poor penetrance across the blood–brain barrier in vivo, we engineered a second-generation chimeric antigen receptor (CAR) T cell therapy against ROBO1, a cell surface receptor enriched across recurrent GBM specimens. A single dose of ROBO1-targeted CAR T cells doubled median survival in cell-line-derived xenograft (CDX) models of recurrent GBM. Moreover, in CDX models of adult lung-to-brain metastases and pediatric relapsed medulloblastoma, ROBO1 CAR T cells eradicated tumors in 50–100% of mice. Our study identifies a promising multi-targetable PTP4A–ROBO1 signaling axis that drives tumorigenicity in recurrent GBM, with potential in other malignant brain tumors.

Published
2024
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30. Haploinsufficiency of RREB1 causes a Noonan-like RASopathy via epigenetic reprogramming of RAS-MAPK pathway genes

Author

Kent, Oliver A., Saha, Manipa, Coyaud, Etienne, Burston, Helen E., Law, Napoleon, Dadson, Keith, Chen, Sujun, Laurent, Estelle M., St-Germain, Jonathan, Sun, Ren X., Matsumoto, Yoshinori, Cowen, Justin, Montgomery-Song, Aaryn, Brown, Kevin R., Ishak, Charles, Rose, Jose La, De Carvalho, Daniel D., He, Housheng Hansen, Raught, Brian, Billia, Filio, Kannu, Peter, and Rottapel, Robert

Published
2020
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31. Inhibition of relaxin autocrine signaling confers therapeutic vulnerability in ovarian cancer

Author

Burston, Helen E., Kent, Oliver A., Communal, Laudine, Udaskin, Molly L., Sun, Ren X., Brown, Kevin R., Jung, Euihye, Francis, Kyle E., La Rose, Jose, Lowitz, Joshua, Drapkin, Ronny, Mes-Masson, Anne-Marie, and Rottapel, Robert

Subjects
Relaxin -- Health aspects, Cellular signal transduction -- Genetic aspects -- Health aspects, Ovarian cancer -- Genetic aspects -- Development and progression -- Care and treatment, Health care industry
Abstract

Ovarian cancer (OC) is the most deadly gynecological malignancy, with unmet clinical need for new therapeutic approaches. The relaxin peptide is a pleiotropic hormone with reproductive functions in the ovary. Relaxin induces cell growth in several types of cancer, but the role of relaxin in OC is poorly understood. Here, using cell lines and xenograft models, we demonstrate that relaxin and its associated GPCR RXFP1 form an autocrine signaling loop essential for OC in vivo tumorigenesis, cell proliferation, and viability. We determined that relaxin signaling activates expression of prooncogenic pathways, including RHO, MAPK, Wnt, and Notch. We found that relaxin is detectable in patient-derived OC tumors, ascites, and serum. Further, inflammatory cytokines IL-6 and TNF-[alpha] activated transcription of relaxin via recruitment of STAT3 and NF-[kappa]B to the proximal promoter, initiating an autocrine feedback loop that potentiated expression. Inhibition of RXFP1 or relaxin increased cisplatin sensitivity of OC cell lines and abrogated in vivo tumor formation. Finally, we demonstrate that a relaxin-neutralizing antibody reduced OC cell viability and sensitized cells to cisplatin. Collectively, these data identify the relaxin/RXFP1 autocrine loop as a therapeutic vulnerability in OC., Introduction Ovarian cancer (OC) has the highest mortality rate of all gynecological malignancies. High-grade serous ovarian carcinoma (HGSOC) is the most common and aggressive subtype, with a dismal 5-year survival [...]

Published
2021
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32. Supplementary Figure Legends from Identification of P450 Oxidoreductase as a Major Determinant of Sensitivity to Hypoxia-Activated Prodrugs

Author

Hunter, Francis W., primary, Young, Richard J., primary, Shalev, Zvi, primary, Vellanki, Ravi N., primary, Wang, Jingli, primary, Gu, Yongchuan, primary, Joshi, Naveen, primary, Sreebhavan, Sreevalsan, primary, Weinreb, Ilan, primary, Goldstein, David P., primary, Moffat, Jason, primary, Ketela, Troy, primary, Brown, Kevin R., primary, Koritzinsky, Marianne, primary, Solomon, Benjamin, primary, Rischin, Danny, primary, Wilson, William R., primary, and Wouters, Bradly G., primary

Published
2023
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33. Supplementary Methods and References from Identification of P450 Oxidoreductase as a Major Determinant of Sensitivity to Hypoxia-Activated Prodrugs

Author

Hunter, Francis W., primary, Young, Richard J., primary, Shalev, Zvi, primary, Vellanki, Ravi N., primary, Wang, Jingli, primary, Gu, Yongchuan, primary, Joshi, Naveen, primary, Sreebhavan, Sreevalsan, primary, Weinreb, Ilan, primary, Goldstein, David P., primary, Moffat, Jason, primary, Ketela, Troy, primary, Brown, Kevin R., primary, Koritzinsky, Marianne, primary, Solomon, Benjamin, primary, Rischin, Danny, primary, Wilson, William R., primary, and Wouters, Bradly G., primary

Published
2023
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34. Supplementary Table S9 from Identification of P450 Oxidoreductase as a Major Determinant of Sensitivity to Hypoxia-Activated Prodrugs

Author

Hunter, Francis W., primary, Young, Richard J., primary, Shalev, Zvi, primary, Vellanki, Ravi N., primary, Wang, Jingli, primary, Gu, Yongchuan, primary, Joshi, Naveen, primary, Sreebhavan, Sreevalsan, primary, Weinreb, Ilan, primary, Goldstein, David P., primary, Moffat, Jason, primary, Ketela, Troy, primary, Brown, Kevin R., primary, Koritzinsky, Marianne, primary, Solomon, Benjamin, primary, Rischin, Danny, primary, Wilson, William R., primary, and Wouters, Bradly G., primary

Published
2023
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35. Data from Identification of P450 Oxidoreductase as a Major Determinant of Sensitivity to Hypoxia-Activated Prodrugs

Author

Hunter, Francis W., primary, Young, Richard J., primary, Shalev, Zvi, primary, Vellanki, Ravi N., primary, Wang, Jingli, primary, Gu, Yongchuan, primary, Joshi, Naveen, primary, Sreebhavan, Sreevalsan, primary, Weinreb, Ilan, primary, Goldstein, David P., primary, Moffat, Jason, primary, Ketela, Troy, primary, Brown, Kevin R., primary, Koritzinsky, Marianne, primary, Solomon, Benjamin, primary, Rischin, Danny, primary, Wilson, William R., primary, and Wouters, Bradly G., primary

Published
2023
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36. Supplementary Figures S1-S14 from Identification of P450 Oxidoreductase as a Major Determinant of Sensitivity to Hypoxia-Activated Prodrugs

Author

Hunter, Francis W., primary, Young, Richard J., primary, Shalev, Zvi, primary, Vellanki, Ravi N., primary, Wang, Jingli, primary, Gu, Yongchuan, primary, Joshi, Naveen, primary, Sreebhavan, Sreevalsan, primary, Weinreb, Ilan, primary, Goldstein, David P., primary, Moffat, Jason, primary, Ketela, Troy, primary, Brown, Kevin R., primary, Koritzinsky, Marianne, primary, Solomon, Benjamin, primary, Rischin, Danny, primary, Wilson, William R., primary, and Wouters, Bradly G., primary

Published
2023
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39. Genome-wide CRISPR screens reveal a Wnt-FZD5 signaling circuit as a druggable vulnerability of RNF43-mutant pancreatic tumors

Author

Steinhart, Zachary, Pavlovic, Zvezdan, Chandrashekhar, Megha, Hart, Traver, Wang, Xiaowei, Zhang, Xiaoyu, Robitaille, Mélanie, Brown, Kevin R, Jaksani, Sridevi, Overmeer, René, Boj, Sylvia F, Adams, Jarrett, Pan, James, Clevers, Hans, Sidhu, Sachdev, Moffat, Jason, and Angers, Stéphane

Subjects
Genetic engineering -- Innovations, Genotypes -- Health aspects, Pancreatic cancer -- Genetic aspects -- Development and progression -- Care and treatment, Cellular signal transduction -- Genetic aspects -- Health aspects, Biological sciences, Health
Abstract

Forward genetic screens with CRISPR-Cas9 genome editing enable high-resolution detection of genetic vulnerabilities in cancer cells. We conducted genome-wide CRISPR-Cas9 screens in RNF43-mutant pancreatic ductal adenocarcinoma (PDAC) cells, which rely on Wnt signaling for proliferation. Through these screens, we discovered a unique requirement for a Wnt signaling circuit: engaging FZD5, one of the ten Frizzled receptors encoded in the human genome. Our results uncover an underappreciated level of context-dependent specificity at the Wnt receptor level. We further derived a panel of recombinant antibodies that reports the expression of nine FZD proteins and confirms that FZD5 functional specificity cannot be explained by protein expression patterns. Additionally, antibodies that specifically bind FZD5 and FZD8 robustly inhibited the growth of RNF43-mutant PDAC cells grown in vitro and as xenografts in vivo, providing orthogonal support for the functional specificity observed genetically. Proliferation of a patient-derived PDAC cell line harboring an RNF43 variant was also selectively inhibited by the FZD5 antibodies, further demonstrating their use as a potential targeted therapy. Tumor organoid cultures from colorectal carcinoma patients that carried RNF43 mutations were also sensitive to the FZD5 antibodies, highlighting the potential generalizability of these findings beyond PDAC. Our results show that CRIPSR-based genetic screens can be leveraged to identify and validate cell surface targets for antibody development and therapy., Author(s): Zachary Steinhart [1]; Zvezdan Pavlovic [2]; Megha Chandrashekhar [2, 3]; Traver Hart [2]; Xiaowei Wang [2, 4]; Xiaoyu Zhang [2, 3]; Mélanie Robitaille [1]; Kevin R Brown [2]; Sridevi [...]

Published
2017
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40. RNAi screen identifies essential regulators of human brain metastasis-initiating cells

Author

Singh, Mohini, Venugopal, Chitra, Tokar, Tomas, Brown, Kevin R., McFarlane, Nicole, Bakhshinyan, David, Vijayakumar, Thusyanth, Manoranjan, Branavan, Mahendram, Sujeivan, Vora, Parvez, Qazi, Maleeha, Dhillon, Manvir, Tong, Amy, Durrer, Kathrin, Murty, Naresh, Hallet, Robin, Hassell, John A., Kaplan, David R., Cutz, Jean-Claude, Jurisica, Igor, Moffat, Jason, and Singh, Sheila K.

Published
2017
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41. Characterization of the minimal residual disease state reveals distinct evolutionary trajectories of human glioblastoma

Author

Qazi, Maleeha A., primary, Salim, Sabra K., additional, Brown, Kevin R., additional, Mikolajewicz, Nicholas, additional, Savage, Neil, additional, Han, Hong, additional, Subapanditha, Minomi K., additional, Bakhshinyan, David, additional, Nixon, Allison, additional, Vora, Parvez, additional, Desmond, Kimberly, additional, Chokshi, Chirayu, additional, Singh, Mohini, additional, Khoo, Amanda, additional, Macklin, Andrew, additional, Khan, Shahbaz, additional, Tatari, Nazanin, additional, Winegarden, Neil, additional, Richards, Laura, additional, Pugh, Trevor, additional, Bock, Nicholas, additional, Mansouri, Alireza, additional, Venugopal, Chitra, additional, Kislinger, Thomas, additional, Goyal, Sidhartha, additional, Moffat, Jason, additional, and Singh, Sheila K., additional

Published
2022
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42. Systematic exploration of dynamic splicing networks reveals conserved multistage regulators of neurogenesis

Author

Han, Hong, primary, Best, Andrew J., additional, Braunschweig, Ulrich, additional, Mikolajewicz, Nicholas, additional, Li, Jack Daiyang, additional, Roth, Jonathan, additional, Chowdhury, Fuad, additional, Mantica, Federica, additional, Nabeel-Shah, Syed, additional, Parada, Guillermo, additional, Brown, Kevin R., additional, O'Hanlon, Dave, additional, Wei, Jiarun, additional, Yao, Yuxi, additional, Zid, Abdelrahman Abou, additional, Comsa, Lim Caden, additional, Jen, Mark, additional, Wang, Jenny, additional, Datti, Alessandro, additional, Gonatopoulos-Pournatzis, Thomas, additional, Weatheritt, Robert J., additional, Greenblatt, Jack F., additional, Wrana, Jeffrey L., additional, Irimia, Manuel, additional, Gingras, Anne-Claude, additional, Moffat, Jason, additional, and Blencowe, Benjamin J., additional

Published
2022
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45. Ontogeny and Vulnerabilities of Drug-Tolerant Persisters in HER2+ Breast Cancer

Author

Chang, Chewei Anderson, primary, Jen, Jayu, additional, Jiang, Shaowen, additional, Sayad, Azin, additional, Mer, Arvind Singh, additional, Brown, Kevin R., additional, Nixon, Allison M.L., additional, Dhabaria, Avantika, additional, Tang, Kwan Ho, additional, Venet, David, additional, Sotiriou, Christos, additional, Deng, Jiehui, additional, Wong, Kwok-kin, additional, Adams, Sylvia, additional, Meyn, Peter, additional, Heguy, Adriana, additional, Skok, Jane A., additional, Tsirigos, Aristotelis, additional, Ueberheide, Beatrix, additional, Moffat, Jason, additional, Singh, Abhyudai, additional, Haibe-Kains, Benjamin, additional, Khodadadi-Jamayran, Alireza, additional, and Neel, Benjamin G., additional

Published
2021
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46. TMOD-15. CHARACTERIZATION OF THE MINIMAL RESIDUAL DISEASE STATE REVEALS DISTINCT EVOLUTIONARY TRAJECTORIES OF HUMAN GLIOBLASTOMA

Author

Qazi, Maleeha, primary, Salim, Sabra, additional, Brown, Kevin R, additional, Savage, Neil, additional, Mickolajewicz, Nicholas, additional, Han, Hong, additional, Chokshi, Chirayu R, additional, Mansouri, Alireza, additional, Venugopal, Chitra, additional, Kislinger, Thomas, additional, Goyal, Sidhartha, additional, Moffat, Jason, additional, and Singh, Sheila K, additional

Published
2021
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47. STEM-05. FUNCTIONAL MAPPING REVEALS WIDESPREAD REMODELLING AND UNRECOGNIZED PATHWAY DEPENDENCIES IN RECURRENT GLIOBLASTOMA

Author

Chokshi, Chirayu R, primary, Tieu, David, additional, Brown, Kevin R, additional, Venugopal, Chitra, additional, Liu, Lina, additional, Kuhlmann, Laura, additional, Rossotti, Martin A, additional, Chan, Katherine, additional, Tong, Amy H Y, additional, Savage, Neil, additional, McKenna, Dillon, additional, Aghaei, Nikoo, additional, Subapanditha, Minomi, additional, Vaseem Shaikh, Muhammad, additional, Tatari, Nazanin, additional, Brakel, Benjamin, additional, Nachmani, Omri, additional, Ignatchenko, Vladimir, additional, Salamoun, Joseph M, additional, Wipf, Peter, additional, Sharlow, Elizabeth, additional, Provias, John P, additional, Lu, Jian-Qiang, additional, Murty, Naresh K, additional, Lazo, John S, additional, Kislinger, Thomas, additional, Henry, Kevin A, additional, Lu, Yu, additional, Moffat, Jason, additional, and Singh, Sheila K, additional

Published
2021
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49. Systematic genome-scale identification of host factors for SARS-CoV-2 infection across models yields a core single gene dependency; ACE2

Author

Chan, Katherine, primary, Farias, Adrian Granda, additional, Lee, Hunsang, additional, Guvenc, Furkan, additional, Mero, Patricia, additional, Aulakh, Kamaldeep, additional, Brown, Kevin R., additional, Haider, Shahan, additional, Marcon, Edyta, additional, Braunschweig, Ulrich, additional, Yan Tong, Amy Hin, additional, Pu, Shuye, additional, Habsid, Andrea, additional, Christie-Holmes, Natasha, additional, Budylowski, Patrick, additional, Astori, Audrey, additional, Ghalami, Ayoob, additional, Mubareka, Samira, additional, Banerjee, Arinjay, additional, Mossman, Karen L., additional, Greenblatt, Jack, additional, Gray-Owen, Scott D., additional, Raught, Brian, additional, Blencowe, Benjamin J., additional, Taipale, Mikko, additional, and Moffat, Jason, additional

Published
2021
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