Modeling familial cancer with induced pluripotent stem cells
Authors: Ruiying Zhao
Weiya Xia
Henia Darr
Dung-Fang Lee
Ye Yuan
Dmitri Papatsenko
Julian Gingold
Razmik Mirzayans
Betty Chang
Ihor R Lemischka
Christoph Schaniel
Mien-Chie Hung
Jie Su
Huen Suk Kim
Journal: Cell (2015)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: in vitro modeling; induced pluripotent stem cell (iPSC) technology; Li-Fraumeni syndrome (LFS); mutant p53; osteosarcoma (OS)
Affiliations: Department of Developmental and Regenerative Biology and The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: ., Department of Developmental and Regenerative Biology and The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Department of Developmental and Regenerative Biology and The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA., Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, AB T6G 1Z2, Canada., Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA; Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung 404, Taiwan., Department of Developmental and Regenerative Biology and The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Department of Developmental and Regenerative Biology and The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: .

Abstract:  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. 

Retracted: No

PubPeer comments:
 Figure 2A - likely identical pattern between graphs (gray dots).  ,