Modeling familial cancer with induced pluripotent stem cells.
Modeling familial cancer with induced pluripotent stem cells.
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DOI：
10.1016/j.cell.2015.02.045
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发表时间：
2015-04-09
期刊：
影响因子：
64.5
通讯作者：
Lemischka IR
中科院分区：
文献类型：
--
作者：
Lee DF;Su J;Kim HS;Chang B;Papatsenko D;Zhao R;Yuan Y;Gingold J;Xia W;Darr H;Mirzayans R;Hung MC;Schaniel C;Lemischka IR
最近，随着诱导多能干细胞(IPSC)技术的发展，人类疾病的体外建模已经成为可能。在这里，我们建立了来自Li-Fraumeni综合征(LFS)家族的患者来源的IPSCs，并研究了突变型P53在骨肉瘤(OS)发生中的作用。LFS IPSC来源的成骨细胞(OBS)概括了OS的特征，包括成骨细胞分化缺陷和致瘤能力。系统分析显示，LFS来源的OBS中丰富的基因表达与肿瘤复发时间的减少和患者较差的生存密切相关。此外，LFSOBS在成骨过程中表现出印记基因H19的上调受损。在LFS OBS中恢复H19的表达促进了成骨细胞的分化并抑制了成瘤潜能。通过将人类印记基因网络(IGN)整合到功能基因组分析中，我们发现H19通过IGN组分核心蛋白(DCN)介导对LFS相关OS的抑制。总之，这些发现证明了用IPSCs研究遗传性人类癌症综合征的可行性。
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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