1. In vivo modeling of metastatic human high-grade serous ovarian cancer in mice
- Author
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Kim, Olga, Park, Eun Young, Klinkebiel, David L, Pack, Svetlana D, Shin, Yong-Hyun, Abdullaev, Zied, Emerson, Robert E, Coffey, Donna M, Kwon, Sun Young, Creighton, Chad J, Kwon, Sanghoon, Chang, Edmund C, Chiang, Theodore, Yatsenko, Alexander N, Chien, Jeremy, Cheon, Dong-Joo, Yang-Hartwich, Yang, Nakshatri, Harikrishna, Nephew, Kenneth P, Behringer, Richard R, Fernández, Facundo M, Cho, Chi-Heum, Vanderhyden, Barbara, Drapkin, Ronny, Bast, Robert C, Miller, Kathy D, Karpf, Adam R, Kim, Jaeyeon, and Kwiatkowski, David J
- Subjects
Ribonuclease III ,DNA Repair ,Knockout ,Primary Cell Culture ,Cystadenocarcinoma ,Drug Resistance ,Antineoplastic Agents ,Drug Screening Assays ,Cell Line ,DEAD-box RNA Helicases ,Mice ,Rare Diseases ,Chromosomal Instability ,Genetics ,Animals ,Humans ,2.1 Biological and endogenous factors ,Neoplasm Metastasis ,Aetiology ,Peritoneal Neoplasms ,Cancer ,Ovarian Neoplasms ,Tumor ,Animal ,PTEN Phosphohydrolase ,Serous ,Antitumor ,Ovarian Cancer ,Disease Models ,Mutation ,Feasibility Studies ,Neoplasm ,Female ,Tumor Suppressor Protein p53 ,Neoplasm Grading ,Developmental Biology - 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.
- Published
- 2020