Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism
Hongyun Zhao, Lifeng Yang, Joelle Baddour, Abhinav Achreja, Vincent Bernard, Tyler J. Moss, Juan C. Marini, Thavisha Tudawe, Elena G. Seviour, F Anthony San Lucas, Héctor M. Álvarez, Sonal Gupta, Sourindra N. Maiti, Laurence J.N. Cooper, Donna M. Peehl, Prahlad T. Ram, Anirban Maitra, Deepak Nagrath
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.