Tumor cell adaptation to nutrient stress via metabolic change due to fibronectin/integrin internalization

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 alphavbeta3 induced by stress could promote tumor cell adaptation to nutrient stress. Here, we show that tumor cell-derived fibronectin (FN), a ligand for alphavbeta3, was also upregulated in response to stress and that FN specifically bound to alphavbeta3 could be internalized providing a survival benefit under nutrient-limited conditions. Nutrient-starved cells either lacking FN or alphavbeta3 expression displayed decreased intracellular glutamine and TCA cycle metabolites leading to cell death. Surprisingly, while integrin alpha5beta1 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 alphavbeta3-mediated uptake of FN mitigate nutrient stress thereby representing a critical property of cancer stem cells.