Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism

TLDR

Cancer-associated fibroblasts are a major component of the tumor microenvironment, and altered cellular metabolism is a hallmark of cancer that has largely been studied through neoplastic cell‑autonomous mechanisms. The study shows that exosomes released by patient‑derived CAFs can reprogram cancer cell metabolism after uptake. CAF‑derived exosomes inhibit mitochondrial oxidative phosphorylation, boost glycolysis and glutamine‑dependent reductive carboxylation, supply amino acids via a macropinocytosis‑like, Kras‑independent route, and deliver intact metabolites that cancer cells use for central carbon metabolism and tumor growth under nutrient stress.

Abstract

Cancer-associated fibroblasts (CAFs) are a major cellular component of tumor microenvironment in most solid cancers. Altered cellular metabolism is a hallmark of cancer, and much of the published literature has focused on neoplastic cell-autonomous processes for these adaptations. We demonstrate that exosomes secreted by patient-derived CAFs can strikingly reprogram the metabolic machinery following their uptake by cancer cells. We find that CAF-derived exosomes (CDEs) inhibit mitochondrial oxidative phosphorylation, thereby increasing glycolysis and glutamine-dependent reductive carboxylation in cancer cells. Through 13C-labeled isotope labeling experiments we elucidate that exosomes supply amino acids to nutrient-deprived cancer cells in a mechanism similar to macropinocytosis, albeit without the previously described dependence on oncogenic-Kras signaling. Using intra-exosomal metabolomics, we provide compelling evidence that CDEs contain intact metabolites, including amino acids, lipids, and TCA-cycle intermediates that are avidly utilized by cancer cells for central carbon metabolism and promoting tumor growth under nutrient deprivation or nutrient stressed conditions.