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

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

doi:10.1016/j.celrep.2021.110146

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

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

Research output: Contribution to journal › Article › peer-review

31 Scopus citations

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 (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.

Original language	English (US)
Article number	110146
Journal	Cell Reports
Volume	37
Issue number	13
DOIs	https://doi.org/10.1016/j.celrep.2021.110146
State	Published - Dec 28 2021
Externally published	Yes

Keywords

carcinogenesis
disease modeling
fallopian tube
induced pluripotent stem cell (iPSC)
ovarian cancer

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2021.110146

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Yucer, N., Ahdoot, R., Workman, M. J., Laperle, A. H., Recouvreux, M. S., Kurowski, K., Naboulsi, D. J., Liang, V., Qu, Y., Plummer, J. T., Gayther, S. A., Orsulic, S., Karlan, B. Y., & Svendsen, C. N. (2021). Human iPSC-derived fallopian tube organoids with BRCA1 mutation recapitulate early-stage carcinogenesis. Cell Reports, 37(13), Article 110146. https://doi.org/10.1016/j.celrep.2021.110146

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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",

author = "Nur Yucer and Rodney Ahdoot and Workman, {Michael J.} and Laperle, {Alexander H.} and Recouvreux, {Maria S.} and Kathleen Kurowski and Naboulsi, {Diana J.} and Victoria Liang and Ying Qu and Plummer, {Jasmine T.} and Gayther, {Simon A.} and Sandra Orsulic and Karlan, {Beth Y.} and Svendsen, {Clive N.}",

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doi = "10.1016/j.celrep.2021.110146",

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AU - Yucer, Nur

AU - Ahdoot, Rodney

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AU - Laperle, Alexander H.

AU - Recouvreux, Maria S.

AU - Kurowski, Kathleen

AU - Naboulsi, Diana J.

AU - Liang, Victoria

AU - Qu, Ying

AU - Plummer, Jasmine T.

AU - Gayther, Simon A.

AU - Orsulic, Sandra

AU - Karlan, Beth Y.

AU - Svendsen, Clive N.

PY - 2021/12/28

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N2 - 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.

AB - 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.

KW - carcinogenesis

KW - disease modeling

KW - fallopian tube

KW - induced pluripotent stem cell (iPSC)

KW - ovarian cancer

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

Abstract

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ASJC Scopus subject areas

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