Cancer stem/tumor-initiating cells display stress tolerance and metabolic flexibility to survive in a harsh environment with limited nutrient and oxygen availability. The molecular mechanisms underlying this phenomenon could provide targets to prevent metabolic adaptation and halt cancer progression. Here, we showed in cultured cells and live human surgical biopsies of non–small cell lung cancer that nutrient stress drives the expression of the epithelial cancer stem cell marker integrin αvβ3 via upregulation of the β3 subunit, resulting in a metabolic reprogramming cascade that allows tumor cells to thrive despite a nutrient-limiting environment. Although nutrient deprivation is known to promote acute, yet transient, activation of the stress sensor AMP-activated protein kinase (AMPK), stress-induced αvβ3 expression via Src activation unexpectedly led to secondary and sustained AMPK activation. This resulted in the nuclear localization of peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC1α) and upregulation of glutamine metabolism, the tricarboxylic acid cycle, and oxidative phosphorylation. Pharmacological or genetic targeting of this axis prevented lung cancer cells from evading the effects of nutrient stress, thereby blocking tumor initiation in mice following orthotopic implantation of lung cancer cells. These findings reveal a molecular pathway driven by nutrient stress that results in cancer stem cell reprogramming to promote metabolic flexibility and tumor initiation. Significance: Upregulation of integrin αvβ3, a cancer stem cell marker, in response to nutrient stress activates sustained AMPK/PGC1α signaling that induces metabolic reprogramming in lung cancer cells to support their survival. See related article by xxxx, p. xx

中文翻译：

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整合素αvβ3响应营养应激的上调促进肺癌细胞代谢可塑性

癌症干/肿瘤起始细胞表现出应激耐受性和代谢灵活性，可以在营养和氧气有限的恶劣环境中生存。这种现象背后的分子机制可以提供阻止代谢适应和阻止癌症进展的目标。在这里，我们在非小细胞肺癌的培养细胞和活体人类手术活检中表明，营养应激通过β3亚基的上调驱动上皮癌干细胞标记物整合素αvβ3的表达，从而导致代谢重编程级联，从而使肿瘤尽管营养有限的环境，细胞仍能茁壮成长。尽管已知营养缺乏会促进应激传感器 AMP 激活蛋白激酶 (AMPK) 的急性但短暂的激活，但通过 Src 激活应激诱导的 αvβ3 表达出乎意料地导致了继发性和持续性 AMPK 激活。这导致过氧化物酶体增殖物激活受体-γ共激活子 1α (PGC1α) 的核定位以及谷氨酰胺代谢、三羧酸循环和氧化磷酸化的上调。该轴的药理学或遗传靶向可防止肺癌细胞逃避营养应激的影响，从而阻止肺癌细胞原位植入小鼠体内肿瘤的发生。这些发现揭示了由营养应激驱动的分子途径，导致癌症干细胞重新编程，以促进代谢灵活性和肿瘤发生。意义：整合素 αvβ3（一种癌症干细胞标记物）在营养应激反应中上调，可激活持续的 AMPK/PGC1α 信号传导，诱导肺癌细胞代谢重编程以支持其生存。参见 xxxx 的相关文章，第 17 页。 xx