Abstract 780: Tumor cell adaptation to nutrient stress via metabolic change due to fibronectin/integrin internalization.

Abstract Tumor cells that adapt to stressors in the microenvironment gain a stem-like, aggressive phenotype, promoting cancer progression and drug resistance. We previously showed that integrin αvβ3 induced by stress could promote tumor cell adaptation to nutrient stress. Here, we show that tumor cell-derived fibronectin (FN), a ligand for αvβ3, was also upregulated in response to stress and that FN specifically bound to αvβ3 could be internalized providing a survival benefit under nutrient-limited conditions. Nutrient-starved cells either lacking FN or αvβ3 expression displayed decreased intracellular glutamine and TCA cycle metabolites leading to cell death. Surprisingly, while integrin α5β1 is the predominant FN receptor on these cells and is critical for cell surface FN localization, it did not promote FN internalization that protected cells from nutrient stress. These findings highlight a novel mechanism by which αvβ3-mediated uptake of FN mitigate nutrient stress thereby representing a critical property of cancer stem cells. Citation Format: Arin Nam, Tasha Nguyen, Tami von Schalscha, Sara M. Weis, David A. Cheresh. Tumor cell adaptation to nutrient stress via metabolic change due to fibronectin/integrin internalization abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 780.