FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy
Gene copy number alterations, tumor cell stemness, and the development of platinum chemotherapy resistance contribute to high-grade serous ovarian cancer (HGSOC) recurrence. Stem phenotypes involving Wnt-β-catenin, aldehyde dehydrogenase activities, intrinsic platinum resistance, and tumorsphere for...
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Language: | English |
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eLife Sciences Publications Ltd
2019-09-01
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Series: | eLife |
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Online Access: | https://elifesciences.org/articles/47327 |
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Article |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Carlos J Diaz Osterman Duygu Ozmadenci Elizabeth G Kleinschmidt Kristin N Taylor Allison M Barrie Shulin Jiang Lisa M Bean Florian J Sulzmaier Christine Jean Isabelle Tancioni Kristen Anderson Sean Uryu Edward A Cordasco Jian Li Xiao Lei Chen Guo Fu Marjaana Ojalill Pekka Rappu Jyrki Heino Adam M Mark Guorong Xu Kathleen M Fisch Vihren N Kolev David T Weaver Jonathan A Pachter Balázs Győrffy Michael T McHale Denise C Connolly Alfredo Molinolo Dwayne G Stupack David D Schlaepfer |
spellingShingle |
Carlos J Diaz Osterman Duygu Ozmadenci Elizabeth G Kleinschmidt Kristin N Taylor Allison M Barrie Shulin Jiang Lisa M Bean Florian J Sulzmaier Christine Jean Isabelle Tancioni Kristen Anderson Sean Uryu Edward A Cordasco Jian Li Xiao Lei Chen Guo Fu Marjaana Ojalill Pekka Rappu Jyrki Heino Adam M Mark Guorong Xu Kathleen M Fisch Vihren N Kolev David T Weaver Jonathan A Pachter Balázs Győrffy Michael T McHale Denise C Connolly Alfredo Molinolo Dwayne G Stupack David D Schlaepfer FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy eLife beta-catenin focal adhesion kinase FAK ovarian cancer platinum chemotherapy pluripotency tumorspheres |
author_facet |
Carlos J Diaz Osterman Duygu Ozmadenci Elizabeth G Kleinschmidt Kristin N Taylor Allison M Barrie Shulin Jiang Lisa M Bean Florian J Sulzmaier Christine Jean Isabelle Tancioni Kristen Anderson Sean Uryu Edward A Cordasco Jian Li Xiao Lei Chen Guo Fu Marjaana Ojalill Pekka Rappu Jyrki Heino Adam M Mark Guorong Xu Kathleen M Fisch Vihren N Kolev David T Weaver Jonathan A Pachter Balázs Győrffy Michael T McHale Denise C Connolly Alfredo Molinolo Dwayne G Stupack David D Schlaepfer |
author_sort |
Carlos J Diaz Osterman |
title |
FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy |
title_short |
FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy |
title_full |
FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy |
title_fullStr |
FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy |
title_full_unstemmed |
FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy |
title_sort |
fak activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy |
publisher |
eLife Sciences Publications Ltd |
series |
eLife |
issn |
2050-084X |
publishDate |
2019-09-01 |
description |
Gene copy number alterations, tumor cell stemness, and the development of platinum chemotherapy resistance contribute to high-grade serous ovarian cancer (HGSOC) recurrence. Stem phenotypes involving Wnt-β-catenin, aldehyde dehydrogenase activities, intrinsic platinum resistance, and tumorsphere formation are here associated with spontaneous gains in Kras, Myc and FAK (KMF) genes in a new aggressive murine model of ovarian cancer. Adhesion-independent FAK signaling sustained KMF and human tumorsphere proliferation as well as resistance to cisplatin cytotoxicity. Platinum-resistant tumorspheres can acquire a dependence on FAK for growth. Accordingly, increased FAK tyrosine phosphorylation was observed within HGSOC patient tumors surviving neo-adjuvant chemotherapy. Combining a FAK inhibitor with platinum overcame chemoresistance and triggered cell apoptosis. FAK transcriptomic analyses across knockout and reconstituted cells identified 135 targets, elevated in HGSOC, that were regulated by FAK activity and β-catenin including Myc, pluripotency and DNA repair genes. These studies reveal an oncogenic FAK signaling role supporting chemoresistance. |
topic |
beta-catenin focal adhesion kinase FAK ovarian cancer platinum chemotherapy pluripotency tumorspheres |
url |
https://elifesciences.org/articles/47327 |
work_keys_str_mv |
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doaj-7193db572cdc40948c8a07915a6afd962021-05-05T17:53:37ZengeLife Sciences Publications LtdeLife2050-084X2019-09-01810.7554/eLife.47327FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapyCarlos J Diaz Osterman0Duygu Ozmadenci1Elizabeth G Kleinschmidt2Kristin N Taylor3Allison M Barrie4Shulin Jiang5Lisa M Bean6Florian J Sulzmaier7Christine Jean8Isabelle Tancioni9Kristen Anderson10Sean Uryu11Edward A Cordasco12Jian Li13Xiao Lei Chen14Guo Fu15Marjaana Ojalill16Pekka Rappu17https://orcid.org/0000-0002-5068-2842Jyrki Heino18Adam M Mark19Guorong Xu20Kathleen M Fisch21Vihren N Kolev22David T Weaver23Jonathan A Pachter24Balázs Győrffy25Michael T McHale26Denise C Connolly27Alfredo Molinolo28Dwayne G Stupack29https://orcid.org/0000-0003-4396-5745David D Schlaepfer30https://orcid.org/0000-0003-4814-9210Department of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United StatesDepartment of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United StatesDepartment of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United StatesDepartment of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United StatesDepartment of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United StatesDepartment of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United StatesDepartment of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United StatesDepartment of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United StatesDepartment of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United StatesDepartment of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United StatesDepartment of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United StatesDepartment of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United StatesDepartment of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United StatesState Key Laboratory of Cellular Stress Biology, Innovation Center for Cellular Signaling Network, School of Life Sciences, Xiamen University, Xiamen, ChinaState Key Laboratory of Cellular Stress Biology, Innovation Center for Cellular Signaling Network, School of Life Sciences, Xiamen University, Xiamen, ChinaState Key Laboratory of Cellular Stress Biology, Innovation Center for Cellular Signaling Network, School of Life Sciences, Xiamen University, Xiamen, ChinaDepartment of Biochemistry, University of Turku, Turku, FinlandDepartment of Biochemistry, University of Turku, Turku, FinlandDepartment of Biochemistry, University of Turku, Turku, FinlandDepartment of Medicine, UCSD Center for Computational Biology & Bioinformatics, La Jolla, United StatesDepartment of Medicine, UCSD Center for Computational Biology & Bioinformatics, La Jolla, United StatesDepartment of Medicine, UCSD Center for Computational Biology & Bioinformatics, La Jolla, United StatesVerastem Oncology, Needham, United StatesVerastem Oncology, Needham, United StatesVerastem Oncology, Needham, United StatesInstitute of Enzymology, Hungarian Academy of Sciences, Budapest, Hungary; 2nd Department of Pediatrics, Semmelweis University, Budapest, HungaryDepartment of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United StatesFox Chase Cancer Center, Philadelphia, United StatesDepartment of Pathology, Moores UCSD Cancer Center, La Jolla, United StatesDepartment of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United StatesDepartment of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United StatesGene copy number alterations, tumor cell stemness, and the development of platinum chemotherapy resistance contribute to high-grade serous ovarian cancer (HGSOC) recurrence. Stem phenotypes involving Wnt-β-catenin, aldehyde dehydrogenase activities, intrinsic platinum resistance, and tumorsphere formation are here associated with spontaneous gains in Kras, Myc and FAK (KMF) genes in a new aggressive murine model of ovarian cancer. Adhesion-independent FAK signaling sustained KMF and human tumorsphere proliferation as well as resistance to cisplatin cytotoxicity. Platinum-resistant tumorspheres can acquire a dependence on FAK for growth. Accordingly, increased FAK tyrosine phosphorylation was observed within HGSOC patient tumors surviving neo-adjuvant chemotherapy. Combining a FAK inhibitor with platinum overcame chemoresistance and triggered cell apoptosis. FAK transcriptomic analyses across knockout and reconstituted cells identified 135 targets, elevated in HGSOC, that were regulated by FAK activity and β-catenin including Myc, pluripotency and DNA repair genes. These studies reveal an oncogenic FAK signaling role supporting chemoresistance.https://elifesciences.org/articles/47327beta-cateninfocal adhesion kinase FAKovarian cancerplatinum chemotherapypluripotencytumorspheres |