eLife (Sep 2019)
FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy
- 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
Affiliations
- Carlos J Diaz Osterman
- Department of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United States
- Duygu Ozmadenci
- Department of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United States
- Elizabeth G Kleinschmidt
- Department of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United States
- Kristin N Taylor
- Department of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United States
- Allison M Barrie
- Department of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United States
- Shulin Jiang
- Department of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United States
- Lisa M Bean
- Department of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United States
- Florian J Sulzmaier
- Department of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United States
- Christine Jean
- Department of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United States
- Isabelle Tancioni
- Department of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United States
- Kristen Anderson
- Department of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United States
- Sean Uryu
- Department of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United States
- Edward A Cordasco
- Department of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United States
- Jian Li
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cellular Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China
- Xiao Lei Chen
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cellular Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China
- Guo Fu
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cellular Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China
- Marjaana Ojalill
- Department of Biochemistry, University of Turku, Turku, Finland
- Pekka Rappu
- ORCiD
- Department of Biochemistry, University of Turku, Turku, Finland
- Jyrki Heino
- Department of Biochemistry, University of Turku, Turku, Finland
- Adam M Mark
- Department of Medicine, UCSD Center for Computational Biology & Bioinformatics, La Jolla, United States
- Guorong Xu
- Department of Medicine, UCSD Center for Computational Biology & Bioinformatics, La Jolla, United States
- Kathleen M Fisch
- Department of Medicine, UCSD Center for Computational Biology & Bioinformatics, La Jolla, United States
- Vihren N Kolev
- Verastem Oncology, Needham, United States
- David T Weaver
- Verastem Oncology, Needham, United States
- Jonathan A Pachter
- Verastem Oncology, Needham, United States
- Balázs Győrffy
- Institute of Enzymology, Hungarian Academy of Sciences, Budapest, Hungary; 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary
- Michael T McHale
- Department of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United States
- Denise C Connolly
- Fox Chase Cancer Center, Philadelphia, United States
- Alfredo Molinolo
- Department of Pathology, Moores UCSD Cancer Center, La Jolla, United States
- Dwayne G Stupack
- ORCiD
- Department of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United States
- David D Schlaepfer
- ORCiD
- Department of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United States
- DOI
- https://doi.org/10.7554/eLife.47327
- Journal volume & issue
-
Vol. 8
Abstract
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.
Keywords
- beta-catenin
- focal adhesion kinase FAK
- ovarian cancer
- platinum chemotherapy
- pluripotency
- tumorspheres
