Unknown,Transcriptomics,Genomics,Proteomics

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Modeling Familial Cancer with iPSC Approaches

ABSTRACT: In vitro modeling of human disease has recently become feasible with the adoption of induced pluripotent stem cell (iPSC) technology. Here, we established patient-derived iPSCs from an Li-Fraumeni Syndrome (LFS) family and investigated the role of mutant p53 in the development of osteosarcoma (OS). Several members of this family carried a heterozygous p53(G245D) mutation and presented with a broad spectrum of tumors including OS. Osteoblasts (OBs) differentiated from iPSC-derived mesenchymal stem cells (MSCs) recapitulated OS features including defective osteoblastic differentiation (OB 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. In silico cytogenetic region enrichment analysis (CREA) demonstrated that LFS-derived OBs do not have genomic rearrangements and hence are a particularly valuable tool for elucidating early oncogenic events prior to the accumulation of secondary alterations. LFS OBs exhibited impaired upregulation of the imprinted gene H19 during osteogenesis. Restoration of H19 expression in LFS OBs facilitated osteogenic differentiation and repressed tumorigenic potential. By integrating human imprinted gene network (IGN) and functional genomic analyses, we found that H19-mediates suppression of LFS-associated OS through the IGN component DECORIN (DCN). Downregulation of DCN impairs H19-mediated osteogenic differentiation and tumor suppression. In summary, these findings demonstrate the feasibility of studying inherited human cancer syndromes with iPSCs and also provide molecular insights into the role of the IGN in p53 mutation-mediated tumorigenesis. mRNAseq profiling during mesenchymal stem cell differentiation to osteoblasts.

ORGANISM(S): Homo sapiens

SUBMITTER: Betty Chang

PROVIDER: E-GEOD-58123 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Modeling familial cancer with induced pluripotent stem cells.

Lee Dung-Fang DF Su Jie J Kim Huen Suk HS Chang Betty B Papatsenko Dmitri D Zhao Ruiying R Yuan Ye Y Gingold Julian J Xia Weiya W Darr Henia H Mirzayans Razmik R Hung Mien-Chie MC Schaniel Christoph C Lemischka Ihor R IR

Cell 20150401 2

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-d ...[more]

PMID: 25860607

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Modeling Familial Cancer with iPSC Approaches

Publications

Modeling familial cancer with induced pluripotent stem cells.

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