In vivo modeling of metastatic human highgrade serous ovarian cancer in mice

Olga Kim; Eun Young Park; David L. Klinkebie; Svetlana D. Pack; Yong Hyun Shin; Zied Abdullaev; Robert E. Emerson; Donna M. Coffey; Sun Young Kwon; Chad J. Creighton; Sanghoon Kwon; Edmund C. Chang; Theodore Chiang; Alexander N. Yatsenko; Jeremy Chien; Dong Joo Cheon; Yang Yang-Hartwich; Harikrishna Nakshatri; Kenneth P. Nephew; Richard R. Behringer; Facundo M. Fernandez; Chi Heum Cho; Barbara Vanderhyden; Ronny Drapkin; Robert C. Bast; Kathy D. Miller; Adam R. Karpf; Jaeyeon Kim

doi:10.1371/journal.pgen.1008808

In vivo modeling of metastatic human highgrade serous ovarian cancer in mice

Olga Kim, Eun Young Park, David L. Klinkebie, Svetlana D. Pack, Yong Hyun Shin, Zied Abdullaev, Robert E. Emerson, Donna M. Coffey, Sun Young Kwon, Chad J. Creighton, Sanghoon Kwon, Edmund C. Chang, Theodore Chiang, Alexander N. Yatsenko, Jeremy Chien, Dong Joo Cheon, Yang Yang-Hartwich, Harikrishna Nakshatri, Kenneth P. Nephew, Richard R. BehringerFacundo M. Fernandez, Chi Heum Cho, Barbara Vanderhyden, Ronny Drapkin, Robert C. Bast, Kathy D. Miller, Adam R. Karpf, Jaeyeon Kim

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Abstract

Metastasis is responsible for 90% of human cancer mortality, yet it remains a challenge to model human cancer metastasis in vivo. Here we describe mouse models of high-grade serous ovarian cancer, also known as high-grade serous carcinoma (HGSC), the most common and deadliest human ovarian cancer type. Mice genetically engineered to harbor Dicer1 and Pten inactivation and mutant p53 robustly replicate the peritoneal metastases of human HGSC with complete penetrance. Arising from the fallopian tube, tumors spread to the ovary and metastasize throughout the pelvic and peritoneal cavities, invariably inducing hemorrhagic ascites. Widespread and abundant peritoneal metastases ultimately cause mouse deaths (100%). Besides the phenotypic and histopathological similarities, mouse HGSCs also display marked chromosomal instability, impaired DNA repair, and chemosensitivity. Faithfully recapitulating the clinical metastases as well as molecular and genomic features of human HGSC, this murine model will be valuable for elucidating the mechanisms underlying the development and progression of metastatic ovarian cancer and also for evaluating potential therapies.

Original language	English (US)
Article number	e1008808
Journal	PLoS genetics
Volume	16
Issue number	6
DOIs	https://doi.org/10.1371/journal.pgen.1008808
State	Published - Jun 2020

ASJC Scopus subject areas

Ecology, Evolution, Behavior and Systematics
Molecular Biology
Genetics
Genetics(clinical)
Cancer Research

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Kim, O., Park, E. Y., Klinkebie, D. L., Pack, S. D., Shin, Y. H., Abdullaev, Z., Emerson, R. E., Coffey, D. M., Kwon, S. Y., Creighton, C. J., Kwon, S., Chang, E. C., Chiang, T., Yatsenko, A. N., Chien, J., Cheon, D. J., Yang-Hartwich, Y., Nakshatri, H., Nephew, K. P., ... Kim, J. (2020). In vivo modeling of metastatic human highgrade serous ovarian cancer in mice. PLoS genetics, 16(6), Article e1008808. https://doi.org/10.1371/journal.pgen.1008808

Kim, O, Park, EY, Klinkebie, DL, Pack, SD, Shin, YH, Abdullaev, Z, Emerson, RE, Coffey, DM, Kwon, SY, Creighton, CJ, Kwon, S, Chang, EC, Chiang, T, Yatsenko, AN, Chien, J, Cheon, DJ, Yang-Hartwich, Y, Nakshatri, H, Nephew, KP, Behringer, RR, Fernandez, FM, Cho, CH, Vanderhyden, B, Drapkin, R, Bast, RC, Miller, KD, Karpf, AR & Kim, J 2020, 'In vivo modeling of metastatic human highgrade serous ovarian cancer in mice', PLoS genetics, vol. 16, no. 6, e1008808. https://doi.org/10.1371/journal.pgen.1008808

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title = "In vivo modeling of metastatic human highgrade serous ovarian cancer in mice",

abstract = "Metastasis is responsible for 90% of human cancer mortality, yet it remains a challenge to model human cancer metastasis in vivo. Here we describe mouse models of high-grade serous ovarian cancer, also known as high-grade serous carcinoma (HGSC), the most common and deadliest human ovarian cancer type. Mice genetically engineered to harbor Dicer1 and Pten inactivation and mutant p53 robustly replicate the peritoneal metastases of human HGSC with complete penetrance. Arising from the fallopian tube, tumors spread to the ovary and metastasize throughout the pelvic and peritoneal cavities, invariably inducing hemorrhagic ascites. Widespread and abundant peritoneal metastases ultimately cause mouse deaths (100%). Besides the phenotypic and histopathological similarities, mouse HGSCs also display marked chromosomal instability, impaired DNA repair, and chemosensitivity. Faithfully recapitulating the clinical metastases as well as molecular and genomic features of human HGSC, this murine model will be valuable for elucidating the mechanisms underlying the development and progression of metastatic ovarian cancer and also for evaluating potential therapies.",

author = "Olga Kim and Park, {Eun Young} and Klinkebie, {David L.} and Pack, {Svetlana D.} and Shin, {Yong Hyun} and Zied Abdullaev and Emerson, {Robert E.} and Coffey, {Donna M.} and Kwon, {Sun Young} and Creighton, {Chad J.} and Sanghoon Kwon and Chang, {Edmund C.} and Theodore Chiang and Yatsenko, {Alexander N.} and Jeremy Chien and Cheon, {Dong Joo} and Yang Yang-Hartwich and Harikrishna Nakshatri and Nephew, {Kenneth P.} and Behringer, {Richard R.} and Fernandez, {Facundo M.} and Cho, {Chi Heum} and Barbara Vanderhyden and Ronny Drapkin and Bast, {Robert C.} and Miller, {Kathy D.} and Karpf, {Adam R.} and Jaeyeon Kim",

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AU - Emerson, Robert E.

AU - Coffey, Donna M.

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AU - Creighton, Chad J.

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AU - Chiang, Theodore

AU - Yatsenko, Alexander N.

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AU - Cheon, Dong Joo

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AU - Nephew, Kenneth P.

AU - Behringer, Richard R.

AU - Fernandez, Facundo M.

AU - Cho, Chi Heum

AU - Vanderhyden, Barbara

AU - Drapkin, Ronny

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AU - Miller, Kathy D.

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AU - Kim, Jaeyeon

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In vivo modeling of metastatic human highgrade serous ovarian cancer in mice

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