Human iPSC-derived fallopian tube organoids with BRCA1 mutation recapitulate early-stage 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 (BRCA1(mut)). Following differentiation into FTE organoids, BRCA1(mut) lines exhibit cellular abnormalities consistent with neoplastic transformation compared to controls. BRCA1(mut) 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 BRCA1(mut) 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.

Automated summary

Germline pathogenic mutations in BRCA1 genes drive normal fallopian tube epithelial cell transformation to high-grade serous ovarian cancer. Induced pluripotent stem cells from individuals with these mutations show neoplastic transformation when differentiated into FTE organoids, indicating a potential value in predicting clinical severity prior to disease onset. This platform can be used for personalized mechanistic and drug screening studies.