Modeling Familial Cancer with Induced Pluripotent Stem Cells

• Published in: Cell 2015-04, Vol.161 (2), p.240-254
• Main Authors: Lee, Dung-Fang, Su, Jie, Kim, Huen Suk, Chang, Betty, Papatsenko, Dmitri, Zhao, Ruiying, Yuan, Ye, Gingold, Julian, Xia, Weiya, Darr, Henia, Mirzayans, Razmik, Hung, Mien-Chie, Schaniel, Christoph, Lemischka, Ihor R.
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Animals; Child; Decorin - metabolism; Female; Gene Regulatory Networks; Humans; Induced Pluripotent Stem Cells - cytology; Li-Fraumeni Syndrome - complications; Li-Fraumeni Syndrome - genetics; Li-Fraumeni Syndrome - pathology; Male; Mesenchymal Stromal Cells - metabolism; Mice; Models, Biological; Neoplasm Transplantation; Osteoblasts - cytology; Osteoblasts - metabolism; Osteogenesis; Osteosarcoma - etiology; Osteosarcoma - genetics; Osteosarcoma - pathology; RNA, Long Noncoding - metabolism; Transplantation, Heterologous; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2015.02.045

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. [Display omitted] [Display omitted] •LFS iPSC-derived OBs recapitulate OS features•LFS iPSC-derived OBs represent OS gene signatures•p53 mutants exert their gain-of-function effects by suppressing H19 expression•Dysregulation of the H19 IGN is involved in LFS-associated OS Li-Fraumeni Syndrome patient-derived iPSCs are used to model human familial cancer, revealing a role of mutant p53 in regulating the imprinted gene network whose dysregulation results in osteoblast differentiation defects and tumorigenesis.