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

• Published in: Cell reports (Cambridge) Vol. 37; no. 13; p. 110146
• Main Authors: Yucer, Nur, Ahdoot, Rodney, Workman, Michael J., Laperle, Alexander H., Recouvreux, Maria S., Kurowski, Kathleen, Naboulsi, Diana J., Liang, Victoria, Qu, Ying, Plummer, Jasmine T., Gayther, Simon A., Orsulic, Sandra, Karlan, Beth Y., Svendsen, Clive N.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28.12.2021
• Subjects: Animals; Apoptosis; BRCA1 Protein - genetics; carcinogenesis; Carcinogenesis - genetics; Carcinogenesis - metabolism; Carcinogenesis - pathology; Case-Control Studies; Cell Differentiation; Cell Proliferation; disease modeling; fallopian tube; Fallopian Tubes - metabolism; Fallopian Tubes - pathology; Female; Germ-Line Mutation; Humans; induced pluripotent stem cell (iPSC); Induced Pluripotent Stem Cells - metabolism; Induced Pluripotent Stem Cells - pathology; Mice; Mice, Nude; Organoids - metabolism; Organoids - pathology; ovarian cancer; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Tumor Cells, Cultured; Xenograft Model Antitumor Assays; induced pluripotent stem cell (iPSC); carcinogenesis; ovarian cancer; fallopian tube; disease modeling
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.110146

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. [Display omitted] •BRCA1mut patient iPSC lines can be differentiated into fallopian tube epithelium•BRCA1mut fallopian tubes recapitulate ovarian carcinogenesis in vitro and in vivo•BRCA1mut fallopian tubes may provide a model to predict disease severity•BRCA1mut fallopian tube organoids provide a platform to study efficacy of cancer drugs Yucer et al. generate a human BRCA1 mutant iPSC-derived fallopian tube organoid model, which recapitulates BRCA1 mutant ovarian carcinogenesis in vitro and shows tumors in vivo. This model provides a biologically relevant platform to validate drugs and a basis for personalized early detection and preventative strategies for women carrying BRCA1 mutations.