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

Cell Rep. 2021 Dec 28;37(13):110146. doi: 10.1016/j.celrep.2021.110146.

Abstract

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.

Keywords: carcinogenesis; disease modeling; fallopian tube; induced pluripotent stem cell (iPSC); ovarian cancer.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis
  • BRCA1 Protein / genetics*
  • Carcinogenesis / genetics
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology*
  • Case-Control Studies
  • Cell Differentiation
  • Cell Proliferation
  • Fallopian Tubes / metabolism
  • Fallopian Tubes / pathology*
  • Female
  • Germ-Line Mutation*
  • Humans
  • Induced Pluripotent Stem Cells / metabolism
  • Induced Pluripotent Stem Cells / pathology*
  • Mice
  • Mice, Nude
  • Organoids / metabolism
  • Organoids / pathology*
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • BRCA1 Protein
  • BRCA1 protein, human