Human iPSC-derived fallopian tube organoids with BRCA1 mutation recapitulate early-stage carcinogenesis

• DOI: 10.1016/j.celrep.2021.110146
• Publication Date: 2021-12-28T19:00:57Z
• Authors: Nur Yucer; Rodney Ahdoot; Michael J. Workman; Alexander H. Laperle; Maria S. Recouvreux; Kathleen Kurowski; Diana J. Naboulsi; Victoria Liang; Ying Qu; Jasmine T. Plummer; Simon A. Gayther; Sandra Orsulic; Beth Y. Karlan; Clive N. Svendsen
• Keywords: induced pluripotent stem cell; Carcinogenesis; Nude; Medical Physiology; Induced Pluripotent Stem Cells; 610; Mice, Nude; Apoptosis; Article; Mice; 03 medical and health sciences; Rare Diseases; Clinical Research; disease modeling; Breast Cancer; Tumor Cells, Cultured; 2.1 Biological and endogenous factors; Animals; Humans; Aetiology; Fallopian Tubes; Germ-Line Mutation; Cancer; Cell Proliferation; Ovarian Neoplasms; fallopian tube; 0303 health sciences; Cultured; Stem Cell Research - Induced Pluripotent Stem Cell - Human; Stem Cell Research - Induced Pluripotent Stem Cell; BRCA1 Protein; Prevention; Cell Differentiation; Stem Cell Research; Xenograft Model Antitumor Assays; Tumor Cells; Ovarian Cancer; 3. Good health; Organoids; ovarian cancer; Good Health and Well Being; Case-Control Studies; Female; Biochemistry and Cell Biology; carcinogenesis

Germline pathogenic mutations in BReast CAncer (BRCA1) genes are thought to drive normal fallopian tube epithelial (FTE) cell transformation to high-grade serous ovarian cancer. No human models capture the sequence of events for disease initiation and progression. Here, we generate induced pluripotent stem cells (iPSCs) from healthy individuals and young ovarian cancer patients with germline pathogenic BRCA1 mutations (BRCA1mut). Following differentiation into FTE organoids, BRCA1mut lines exhibit cellular abnormalities consistent with neoplastic transformation compared to controls. BRCA1mut organoids show an increased production of cancer-specific proteins and survival following transplantation into mice. Organoids from women with the most aggressive ovarian cancer show the greatest pathology, indicating the potential value to predict clinical severity prior to disease onset. These human FTE organoids from BRCA1mut carriers provide a faithful physiological in vitro model of FTE lesion generation and early carcinogenesis. This platform can be used for personalized mechanistic and drug screening studies.