Modeling familial cancer with induced pluripotent stem cells

Dung Fang Lee; Jie Su; Huen Suk Kim; Betty Chang; Dmitri Papatsenko; Ruiying Zhao; Ye Yuan; Julian Gingold; Weiya Xia; Henia Darr; Razmik Mirzayans; Mien Chie Hung; Christoph Schaniel; Ihor R. Lemischka

doi:10.1016/j.cell.2015.02.045

Modeling familial cancer with induced pluripotent stem cells

Dung Fang Lee, Jie Su, Huen Suk Kim, Betty Chang, Dmitri Papatsenko, Ruiying Zhao, Ye Yuan, Julian Gingold, Weiya Xia, Henia Darr, Razmik Mirzayans, Mien Chie Hung, Christoph Schaniel, Ihor R. Lemischka

Molecular & Cellular Oncology

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

157 Scopus citations

Abstract

Summary In vitro modeling of human disease has recently become feasible with induced pluripotent stem cell (iPSC) technology. Here, we established patient-derived iPSCs from a Li-Fraumeni syndrome (LFS) family and investigated the role of mutant p53 in the development of osteosarcoma (OS). LFS iPSC-derived osteoblasts (OBs) recapitulated OS features including defective osteoblastic differentiation as well as tumorigenic ability. Systematic analyses revealed that the expression of genes enriched in LFS-derived OBs strongly correlated with decreased time to tumor recurrence and poor patient survival. Furthermore, LFS OBs exhibited impaired upregulation of the imprinted gene H19 during osteogenesis. Restoration of H19 expression in LFS OBs facilitated osteoblastic differentiation and repressed tumorigenic potential. By integrating human imprinted gene network (IGN) into functional genomic analyses, we found that H19 mediates suppression of LFS-associated OS through the IGN component DECORIN (DCN). In summary, these findings demonstrate the feasibility of studying inherited human cancer syndromes with iPSCs.

Original language	English (US)
Pages (from-to)	240-254
Number of pages	15
Journal	Cell
Volume	161
Issue number	2
DOIs	https://doi.org/10.1016/j.cell.2015.02.045
State	Published - Apr 9 2015

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2015.02.045

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title = "Modeling familial cancer with induced pluripotent stem cells",

abstract = "Summary In vitro modeling of human disease has recently become feasible with induced pluripotent stem cell (iPSC) technology. Here, we established patient-derived iPSCs from a Li-Fraumeni syndrome (LFS) family and investigated the role of mutant p53 in the development of osteosarcoma (OS). LFS iPSC-derived osteoblasts (OBs) recapitulated OS features including defective osteoblastic differentiation as well as tumorigenic ability. Systematic analyses revealed that the expression of genes enriched in LFS-derived OBs strongly correlated with decreased time to tumor recurrence and poor patient survival. Furthermore, LFS OBs exhibited impaired upregulation of the imprinted gene H19 during osteogenesis. Restoration of H19 expression in LFS OBs facilitated osteoblastic differentiation and repressed tumorigenic potential. By integrating human imprinted gene network (IGN) into functional genomic analyses, we found that H19 mediates suppression of LFS-associated OS through the IGN component DECORIN (DCN). In summary, these findings demonstrate the feasibility of studying inherited human cancer syndromes with iPSCs.",

author = "Lee, {Dung Fang} and Jie Su and Kim, {Huen Suk} and Betty Chang and Dmitri Papatsenko and Ruiying Zhao and Ye Yuan and Julian Gingold and Weiya Xia and Henia Darr and Razmik Mirzayans and Hung, {Mien Chie} and Christoph Schaniel and Lemischka, {Ihor R.}",

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year = "2015",

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doi = "10.1016/j.cell.2015.02.045",

language = "English (US)",

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T1 - Modeling familial cancer with induced pluripotent stem cells

AU - Lee, Dung Fang

AU - Su, Jie

AU - Kim, Huen Suk

AU - Chang, Betty

AU - Papatsenko, Dmitri

AU - Zhao, Ruiying

AU - Yuan, Ye

AU - Gingold, Julian

AU - Xia, Weiya

AU - Darr, Henia

AU - Mirzayans, Razmik

AU - Hung, Mien Chie

AU - Schaniel, Christoph

AU - Lemischka, Ihor R.

PY - 2015/4/9

Y1 - 2015/4/9

N2 - Summary In vitro modeling of human disease has recently become feasible with induced pluripotent stem cell (iPSC) technology. Here, we established patient-derived iPSCs from a Li-Fraumeni syndrome (LFS) family and investigated the role of mutant p53 in the development of osteosarcoma (OS). LFS iPSC-derived osteoblasts (OBs) recapitulated OS features including defective osteoblastic differentiation as well as tumorigenic ability. Systematic analyses revealed that the expression of genes enriched in LFS-derived OBs strongly correlated with decreased time to tumor recurrence and poor patient survival. Furthermore, LFS OBs exhibited impaired upregulation of the imprinted gene H19 during osteogenesis. Restoration of H19 expression in LFS OBs facilitated osteoblastic differentiation and repressed tumorigenic potential. By integrating human imprinted gene network (IGN) into functional genomic analyses, we found that H19 mediates suppression of LFS-associated OS through the IGN component DECORIN (DCN). In summary, these findings demonstrate the feasibility of studying inherited human cancer syndromes with iPSCs.

AB - Summary In vitro modeling of human disease has recently become feasible with induced pluripotent stem cell (iPSC) technology. Here, we established patient-derived iPSCs from a Li-Fraumeni syndrome (LFS) family and investigated the role of mutant p53 in the development of osteosarcoma (OS). LFS iPSC-derived osteoblasts (OBs) recapitulated OS features including defective osteoblastic differentiation as well as tumorigenic ability. Systematic analyses revealed that the expression of genes enriched in LFS-derived OBs strongly correlated with decreased time to tumor recurrence and poor patient survival. Furthermore, LFS OBs exhibited impaired upregulation of the imprinted gene H19 during osteogenesis. Restoration of H19 expression in LFS OBs facilitated osteoblastic differentiation and repressed tumorigenic potential. By integrating human imprinted gene network (IGN) into functional genomic analyses, we found that H19 mediates suppression of LFS-associated OS through the IGN component DECORIN (DCN). In summary, these findings demonstrate the feasibility of studying inherited human cancer syndromes with iPSCs.

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Modeling familial cancer with induced pluripotent stem cells

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