FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy

Carlos Díaz 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

doi:10.7554/eLife.47327

FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy

Carlos Díaz 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. MarkGuorong 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

Research output: Contribution to journal › Article › peer-review

86 Scopus citations

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.

Original language	English
Article number	e47327
Journal	eLife
Volume	8
DOIs	https://doi.org/10.7554/eLife.47327
State	Published - Sep 2019

Keywords

Animals
Antineoplastic Agents/pharmacology
Cisplatin/pharmacology
Disease Models, Animal
Drug Resistance, Neoplasm
Female
Focal Adhesion Kinase 1/metabolism
Humans
Mice
Ovarian Neoplasms/drug therapy
Platinum/pharmacology
Proto-Oncogene Proteins c-myc/metabolism
Proto-Oncogene Proteins p21(ras)/metabolism
Signal Transduction
Stem Cells

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.7554/eLife.47327

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Osterman, C. D., Ozmadenci, D., Kleinschmidt, E. G., Taylor, K. N., Barrie, A. M., Jiang, S., Bean, L. M., Sulzmaier, F. J., Jean, C., Tancioni, I., Anderson, K., Uryu, S., Cordasco, E. A., Li, J., Chen, X. L., Fu, G., Ojalill, M., Rappu, P., Heino, J., ... Schlaepfer, D. D. (2019). FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy. eLife, 8, Article e47327. https://doi.org/10.7554/eLife.47327

@article{67e17a7060cc4d558dd45e16d6a89a03,

title = "FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy",

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 = "Animals, Antineoplastic Agents/pharmacology, Cisplatin/pharmacology, Disease Models, Animal, Drug Resistance, Neoplasm, Female, Focal Adhesion Kinase 1/metabolism, Humans, Mice, Ovarian Neoplasms/drug therapy, Platinum/pharmacology, Proto-Oncogene Proteins c-myc/metabolism, Proto-Oncogene Proteins p21(ras)/metabolism, Signal Transduction, Stem Cells",

author = "Osterman, {Carlos D{\'i}az} and Duygu Ozmadenci and Kleinschmidt, {Elizabeth G.} and Taylor, {Kristin N.} and Barrie, {Allison M.} and Shulin Jiang and Bean, {Lisa M.} and Sulzmaier, {Florian J.} and Christine Jean and Isabelle Tancioni and Kristen Anderson and Sean Uryu and Cordasco, {Edward A.} and Jian Li and Chen, {Xiao Lei} and Guo Fu and Marjaana Ojalill and Pekka Rappu and Jyrki Heino and Mark, {Adam M.} and Guorong Xu and Fisch, {Kathleen M.} and Kolev, {Vihren N.} and Weaver, {David T.} and Pachter, {Jonathan A.} and Bal{\'a}zs Gy{\H o}rffy and McHale, {Michael T.} and Connolly, {Denise C.} and Alfredo Molinolo and Stupack, {Dwayne G.} and Schlaepfer, {David D.}",

note = "Publisher Copyright: {\textcopyright} Diaz Osterman et al.",

year = "2019",

month = sep,

doi = "10.7554/eLife.47327",

language = "English",

volume = "8",

journal = "eLife",

issn = "2050-084X",

publisher = "eLife Sciences Publications",

}

Osterman, CD, Ozmadenci, D, Kleinschmidt, EG, Taylor, KN, Barrie, AM, Jiang, S, Bean, LM, Sulzmaier, FJ, Jean, C, Tancioni, I, Anderson, K, Uryu, S, Cordasco, EA, Li, J, Chen, XL, Fu, G, Ojalill, M, Rappu, P, Heino, J, Mark, AM, Xu, G, Fisch, KM, Kolev, VN, Weaver, DT, Pachter, JA, Győrffy, B, McHale, MT, Connolly, DC, Molinolo, A, Stupack, DG & Schlaepfer, DD 2019, 'FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy', eLife, vol. 8, e47327. https://doi.org/10.7554/eLife.47327

TY - JOUR

T1 - FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy

AU - Osterman, Carlos Díaz

AU - Ozmadenci, Duygu

AU - Kleinschmidt, Elizabeth G.

AU - Taylor, Kristin N.

AU - Barrie, Allison M.

AU - Jiang, Shulin

AU - Bean, Lisa M.

AU - Sulzmaier, Florian J.

AU - Jean, Christine

AU - Tancioni, Isabelle

AU - Anderson, Kristen

AU - Uryu, Sean

AU - Cordasco, Edward A.

AU - Li, Jian

AU - Chen, Xiao Lei

AU - Fu, Guo

AU - Ojalill, Marjaana

AU - Rappu, Pekka

AU - Heino, Jyrki

AU - Mark, Adam M.

AU - Xu, Guorong

AU - Fisch, Kathleen M.

AU - Kolev, Vihren N.

AU - Weaver, David T.

AU - Pachter, Jonathan A.

AU - Győrffy, Balázs

AU - McHale, Michael T.

AU - Connolly, Denise C.

AU - Molinolo, Alfredo

AU - Stupack, Dwayne G.

AU - Schlaepfer, David D.

N1 - Publisher Copyright: © Diaz Osterman et al.

PY - 2019/9

Y1 - 2019/9

N2 - 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.

AB - 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.

KW - Animals

KW - Antineoplastic Agents/pharmacology

KW - Cisplatin/pharmacology

KW - Disease Models, Animal

KW - Drug Resistance, Neoplasm

KW - Female

KW - Focal Adhesion Kinase 1/metabolism

KW - Humans

KW - Mice

KW - Ovarian Neoplasms/drug therapy

KW - Platinum/pharmacology

KW - Proto-Oncogene Proteins c-myc/metabolism

KW - Proto-Oncogene Proteins p21(ras)/metabolism

KW - Signal Transduction

KW - Stem Cells

UR - http://www.scopus.com/inward/record.url?scp=85071765259&partnerID=8YFLogxK

U2 - 10.7554/eLife.47327

DO - 10.7554/eLife.47327

M3 - Article

C2 - 31478830

SN - 2050-084X

VL - 8

JO - eLife

JF - eLife

M1 - e47327

ER -

FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy

Abstract

Keywords

UN SDGs

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FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy

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