Epigenetic states of cells of origin and tumor evolution drive tumor-initiating cell phenotype and tumor heterogeneity.
Epigenetic states of cells of origin and tumor evolution drive tumor-initiating cell phenotype and tumor heterogeneity.
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DOI：
10.1158/0008-5472.can-13-3293
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发表时间：
2014-09-01
期刊：
影响因子：
11.2
通讯作者：
Yun K
中科院分区：
文献类型：
--
作者：
Chow KH;Shin DM;Jenkins MH;Miller EE;Shih DJ;Choi S;Low BE;Philip V;Rybinski B;Bronson RT;Taylor MD;Yun K
靶向治疗发展中的一个中心混杂因素是肿瘤细胞的异质性，包括临床相同肿瘤中的肿瘤起始细胞(TIC)。在这里，我们展示了Sonic Hedgehog(SHH)通路在神经干细胞和祖细胞中的激活如何为肿瘤细胞进化到组织上无法区分但在分子上截然不同的异质状态创造了基础。在补丁(PTCH)+/−小鼠中出现的自发性髓母细胞瘤中，我们鉴定了三种不同的肿瘤亚型。通过体内SHH通路的细胞类型特异性激活，我们确定了不同来源的细胞以独特的方式进化来产生这些亚型。此外，每个亚型的抽动具有不同的分子和细胞表型。在整体肿瘤水平上，可以通过465基因信号以及ERK和AKT通路的不同激活水平来区分这三种肿瘤亚型。值得注意的是，不同亚型的抽搐对SHH或AKT途径抑制剂的敏感性不同，这突显了靶向治疗耐药的新机制。综上所述，我们的结果显示了进化过程如何作用于不同来源的细胞，从而在整体肿瘤和TIC水平上促进肿瘤的异质性。
A central confounding factor in the development of targeted therapies is tumor cell heterogeneity, including as it occurs in tumor-initiating cells (TIC) within clinically identical tumors. Here we show how activation of the Sonic Hedgehog (SHH) pathway in neural stem and progenitor cells creates a foundation for tumor cell evolution to heterogeneous states that are histologically indistinguishable but molecularly distinct. In spontaneous medulloblastomas that arise in Patched (Ptch)+/− mice, we identified three distinct tumor subtypes. Through cell type-specific activation of the SHH pathway in vivo, we determined that different cells of origin evolved in unique ways to generate these subtypes. Moreover, TICs in each subtype had distinct molecular and cellular phenotypes. At the bulk tumor level, the three tumor subtypes could be distinguished by a 465-gene signature and by differential activation levels of the ERK and AKT pathways. Notably, TICs from different subtypes were differentially sensitive to SHH or AKT pathway inhibitors, highlighting new mechanisms of resistance to targeted therapies. In summary, our results show how evolutionary processes act on distinct cells of origin to contribute to tumoral heterogeneity, at both bulk tumor and TIC levels.