Abstract 3066: Lung cancer cells overcome nutrient stress by upregulating an integrin αvβ3/AMPK/OXPHOS axis

Abstract Tumor cells are exposed to various forms of stress within the tumor microenvironment, and those cells that adapt often gain stem-like properties that facilitate tumor initiation and metastasis. Here, we show that lung cancer cells exposed to nutrient stress adapt and survive by converting their metabolism from glycolytic to oxidative phosphorylation (OXPHOS). This is based on the cell’s ability to upregulate expression of integrin αvβ3, a driver of tumor initiation, progression, and drug resistance. Mechanistically, integrin αvβ3 recruits and activates c-Src, promoting sustained AMPK activity leading to activation of PGC-1α, which promotes the expression of mitochondrial OXPHOS complexes. In fact, ectopic expression of integrin β3 was sufficient to drive OXPHOS-dependent metabolism even in the absence of stress. Furthermore, pharmacological targeting of this pathway not only rendered integrin αvβ3+ cells sensitive to nutrient depletion but also prevented their ability to undergo tumor initiation. These findings reveal that targeting integrin αvβ3 or its pathway can prevent cancer cell metabolic flexibility and their capacity to adapt to stress within the tumor microenvironment. Citation Format: Arin Nam, Shashi Jain, Alejandro Campos, Ryan M. Shepard, Tami von Schalscha, Sara M. Weis, Hiromi I. Wettersten, David A. Cheresh. Lung cancer cells overcome nutrient stress by upregulating an integrin αvβ3/AMPK/OXPHOS axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3066.