Metabolic stress induces a Wnt-dependent cancer stem cell-like state transition.
Metabolic stress induces a Wnt-dependent cancer stem cell-like state transition.
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DOI：
10.1038/cddis.2015.171
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发表时间：
2015-07-02
影响因子：
9
通讯作者：
Cheong JH
中科院分区：
文献类型：
--
作者：
Lee E;Yang J;Ku M;Kim NH;Park Y;Park CB;Suh JS;Park ES;Yook JI;Mills GB;Huh YM;Cheong JH
癌细胞和肿瘤微环境之间的相互作用驱动多种临床上重要的行为，包括休眠、侵袭和转移以及治疗抗性。这些微环境依赖性表型与癌症干细胞（CSC）具有典型特征。然而，人们对封闭的肿瘤微环境中的代谢应激如何有助于CSC样表型的出现和维持知之甚少。在这里，我们证明了长期营养剥夺中的慢性代谢应激（CMS）诱导非干细胞癌细胞向干细胞样状态的Wnt依赖性表型转化，这反映在转录组分析中。添加Wnt 3a以及转染显性阴性Tcf 4建立了Wnt途径在响应代谢应激获得CSC样特征中的强制性作用。此外，多个单细胞衍生克隆的系统表征和CD 44 +/ESA+干细胞样癌细胞的阴性富集（所有这些都概括了干细胞样癌特征）表明随机适应而不是选择预先存在的亚克隆。最后，肿瘤微环境中的CMS可以通过依赖于Wnt途径的随机状态转换来驱动非干细胞癌细胞的CSC样表型转化。这些发现有助于理解肿瘤代谢微环境中非干细胞癌细胞向干细胞样状态的代谢应激驱动的动态转变。
Reciprocal interactions between cancer cells and the tumor microenvironment drive multiple clinically significant behaviors including dormancy, invasion, and metastasis as well as therapy resistance. These microenvironment-dependent phenotypes share typical characteristics with cancer stem cells (CSC). However, it is poorly understood how metabolic stress in the confined tumor microenvironment contributes to the emergence and maintenance of CSC-like phenotypes. Here, we demonstrate that chronic metabolic stress (CMS) in a long-term nutrient deprivation induces a Wnt-dependent phenoconversion of non-stem cancer cells toward stem-like state and this is reflected in the transcriptome analysis. Addition of Wnt3a as well as transfection of dominant-negative Tcf4 establishes an obligatory role for the Wnt pathway in the acquisition of CSC-like characteristics in response to metabolic stress. Furthermore, systematic characterization for multiple single cell-derived clones and negative enrichment of CD44+/ESA+ stem-like cancer cells, all of which recapitulate stem-like cancer characteristics, suggest stochastic adaptation rather than selection of pre-existing subclones. Finally, CMS in the tumor microenvironment can drive a CSC-like phenoconversion of non-stem cancer cells through stochastic state transition dependent on the Wnt pathway. These findings contribute to an understanding of the metabolic stress-driven dynamic transition of non-stem cancer cells to a stem-like state in the tumor metabolic microenvironment.