TGF-β promotes heterogeneity and drug resistance in squamous cell carcinoma.
TGF-β promotes heterogeneity and drug resistance in squamous cell carcinoma.
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DOI：
10.1016/j.cell.2015.01.043
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发表时间：
2015-02-26
期刊：
影响因子：
64.5
通讯作者：
Fuchs E
中科院分区：
文献类型：
--
作者：
Oshimori N;Oristian D;Fuchs E
长寿的肿瘤起始干细胞亚群常常逃避癌症治疗。然而，产生肿瘤异质性和耐药细胞群的来源和机制仍在探索中。在这里，我们设计了一个功能报告系统，用于 TGF-β 激活的鳞状细胞癌干细胞 (SCC-SC) 中的谱系追踪和/或遗传消融信号传导。通过剖析 TGF-β 对恶性进展的影响，我们证明 TGF-β 集中在肿瘤脉管系统附近，在肿瘤-基质界面处的 TGF-β 信号传导中产生异质性，并赋予邻近 SCC-SC 较慢的循环特性。虽然无反应的子代增殖更快并加速肿瘤生长，但 TGF-β 反应的子代会侵入、异常分化并影响基因表达。有趣的是，TGF-β反应的 SCC-SCs 显示出增强的抗癌药物保护作用，但仅靠较慢的循环并不能带来生存。相反，TGF-β 转录激活 p21，从而稳定 NRF2，从而显着增强谷胱甘肽代谢并降低抗癌治疗的有效性。总之，这些发现为 TGF-β 信号传导建立了令人惊讶的非遗传范例，以促进 SCC-SC 的异质性、肿瘤特征和耐药性。
Subsets of long-lived, tumor-initiating stem cells often escape cancer therapies. However, sources and mechanisms that generate tumor heterogeneity and drug-resistant cell population are still unfolding. Here, we devise a functional reporter system to lineage trace and/or genetic ablate signaling in TGF-β-activated squamous cell carcinoma stem cells (SCC-SCs). Dissecting TGF-β’s impact on malignant progression, we demonstrate that TGF-β concentrating near tumor-vasculature generates heterogeneity in TGF-β signaling at tumor-stroma interface and bestows slower-cycling properties to neighboring SCC-SCs. While non-responding progenies proliferate faster and accelerate tumor growth, TGF-β-responding progenies invade, aberrantly differentiate, and affect gene expression. Intriguingly, TGF-β-responding SCC-SCs show increased protection against anti-cancer drugs, but slower-cycling alone does not confer survival. Rather, TGF-β transcriptionally activates p21, which stabilizes NRF2, thereby markedly enhancing glutathione metabolism and diminishing effectiveness of anti-cancer therapeutics. Together, these findings establish a surprising non-genetic paradigm for TGF-β signaling in fueling heterogeneity in SCC-SCs, tumor characteristics, and drug resistance.