Department of Pathology, Moores Cancer Center, and Sanford Consortium for Regenerative Medicine at the University of California, San Diego, La Jolla, California.
Department of Neurology, University of California, Irvine, Irvine, California.
Cancer Res. 2024 May 15;84(10):1630-1642. doi: 10.1158/0008-5472.CAN-23-2700.
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.
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 commentary by Rainero, p. 1543.
肿瘤起始细胞具有应激耐受和代谢灵活性，可在营养和氧气有限的恶劣环境中生存。这种现象的分子机制可以为预防代谢适应和阻止癌症进展提供靶点。在这里，我们在培养细胞和非小细胞肺癌的活人体外科活检中表明，营养应激通过上调β3 亚基驱动上皮肿瘤起始细胞标志物整合素αvβ3 的表达，导致代谢重编程级联反应，使肿瘤细胞能够在营养有限的环境中茁壮成长。尽管众所周知，营养剥夺会促进应激传感器 AMP 激活蛋白激酶（AMPK）的急性短暂激活，但应激通过Src 激活诱导的αvβ3 表达却导致 AMPK 的二次和持续激活。这导致过氧化物酶体增殖物激活受体γ共激活因子 1α（PGC1α）的核定位和谷氨酰胺代谢、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阻止了肺癌细胞逃避营养应激的影响，从而阻止了肺癌细胞原位植入后小鼠肿瘤的起始。这些发现揭示了一条由营养应激驱动的分子途径，导致癌症起始细胞重编程，以促进代谢灵活性和肿瘤起始。
营养应激反应中整合素αvβ3 的上调，作为肿瘤起始细胞的标志物，激活持续的 AMPK/PGC1α 信号通路，诱导肺癌细胞的代谢重编程，以支持其存活。见 Rainero 的相关评论，第 1543 页。
