| Title: |
FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy |
| Authors: |
Diaz Osterman, Carlos; Ozmadenci, Duygu; Kleinschmidt, Elizabeth; Taylor, Kristin; Barrie, Allison; Jiang, Shulin; Bean, Lisa; Sulzmaier, Florian; Jean, Christine; Tancioni, Isabelle; Anderson, Kristen; Uryu, Sean; Cordasco, Edward; Li, Jian; Chen, Xiao Lei; Fu, Guo; Ojalill, Marjaana; Rappu, Pekka; Heino, Jyrki; Mark, Adam; Xu, Guorong; Fisch, Kathleen; Kolev, Vihren; Weaver, David; Pachter, Jonathan; Győrffy, Balázs; Mchale, Michael; Connolly, Denise; Molinolo, Alfredo; Stupack, Dwayne; Schlaepfer, David |
| Contributors: |
Centre de Recherches en Cancérologie de Toulouse (CRCT); Université Toulouse III - Paul Sabatier (UT3); Communauté d'universités et établissements de Toulouse (Comue de Toulouse)-Communauté d'universités et établissements de Toulouse (Comue de Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS); Real time and interoperability (TRIO); INRIA Lorraine; Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA); Institut National de Recherche en Informatique et en Automatique (Inria)-Université Henri Poincaré - Nancy 1 (UHP)-Université Nancy 2-Institut National Polytechnique de Lorraine (INPL)-Centre National de la Recherche Scientifique (CNRS)-Université Henri Poincaré - Nancy 1 (UHP)-Université Nancy 2-Institut National Polytechnique de Lorraine (INPL)-Centre National de la Recherche Scientifique (CNRS); Texas A&M University College Station; University of Turku; University of California (UC) |
| Source: |
EISSN: 2050-084X ; eLife ; https://hal.science/hal-04823560 ; eLife, 2019, 8 (21), ⟨10.7554/eLife.47327⟩ |
| Publisher Information: |
CCSD; eLife Sciences Publication |
| Publication Year: |
2019 |
| Collection: |
Université de Lorraine: HAL |
| Subject Terms: |
Gastroenterology; Cancer; cancer biology; Oncology; Translation; beta-catenin; tumorspheres; pluripotency; platinum chemotherapy; ovarian cancer; mouse; focal adhesion kinase FAK; MESH: Animals; MESH: Antineoplastic Agents; MESH: Platinum; MESH: Proto-Oncogene Proteins c-myc; MESH: Proto-Oncogene Proteins p21(ras); MESH: Signal Transduction; MESH: Stem Cells; MESH: Cisplatin; MESH: Disease Models; Animal; MESH: Drug Resistance; Neoplasm; MESH: Female; MESH: Focal Adhesion Kinase 1; MESH: Humans; MESH: Mice; MESH: Ovarian Neoplasms; [SDV.BC]Life Sciences [q-bio]/Cellular Biology |
| Description: |
International audience ; 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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/31478830; PUBMED: 31478830; PUBMEDCENTRAL: PMC6721800 |
| DOI: |
10.7554/eLife.47327 |
| Availability: |
https://hal.science/hal-04823560; https://doi.org/10.7554/eLife.47327 |
| Accession Number: |
edsbas.1167455 |
| Database: |
BASE |