The effects of restricted glycolysis on stem-cell like characteristics of breast cancer cells.
The effects of restricted glycolysis on stem-cell like characteristics of breast cancer cells.
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DOI：
10.18632/oncotarget.25299
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发表时间：
2018-05-01
期刊：
影响因子：
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通讯作者：
Blaydes JP
中科院分区：
文献类型：
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作者：
Banerjee A;Arvinrad P;Darley M;Laversin SA;Parker R;Rose-Zerilli MJJ;Townsend PA;Cutress RI;Beers SA;Houghton FD;Birts CN;Blaydes JP
糖酵解改变是许多癌症的特征，也可能与干细胞样癌（SCLC）细胞群的变化有关。因此，我们开始直接研究糖酵解对SCLC细胞表型的影响，使用一种模型，其中糖酵解通过使细胞适应葡萄糖以外的糖源而稳定减少。使用这种方法限制糖酵解一致地导致具有增加的致癌潜力的细胞;包括SCLC细胞的增加、3D基质胶中的增殖、侵袭性、化学抗性和改变的整体基因表达。体内致瘤性也明显增加。SCLC细胞表现出对替代代谢途径的依赖性增加。它们也成为c-KIT依赖性的，表明它们的表观成熟状态受糖酵解调节。单细胞mRNA测序鉴定了响应糖酵解限制的SCLC富集群体内代谢、干细胞和信号传导基因表达的改变网络。因此，糖酵解减少，这可能发生在肿瘤内的小生境中，其中葡萄糖的可用性是有限的，可以通过增加SCLC细胞群来促进肿瘤的侵袭性，但也可以在SCLC细胞中引入新的，潜在的可利用的弱点。
Altered glycolysis is a characteristic of many cancers, and can also be associated with changes in stem cell-like cancer (SCLC) cell populations. We therefore set out to directly examine the effect of glycolysis on SCLC cell phenotype, using a model where glycolysis is stably reduced by adapting the cells to a sugar source other than glucose. Restricting glycolysis using this approach consistently resulted in cells with increased oncogenic potential; including an increase in SCLC cells, proliferation in 3D matrigel, invasiveness, chemoresistance, and altered global gene expression. Tumorigenicity in vivo was also markedly increased. SCLC cells exhibited increased dependence upon alternate metabolic pathways. They also became c-KIT dependent, indicating that their apparent state of maturation is regulated by glycolysis. Single-cell mRNA sequencing identified altered networks of metabolic-, stem- and signaling- gene expression within SCLC-enriched populations in response to glycolytic restriction. Therefore, reduced glycolysis, which may occur in niches within tumors where glucose availability is limiting, can promote tumor aggressiveness by increasing SCLC cell populations, but can also introduce novel, potentially exploitable, vulnerabilities in SCLC cells.