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Title: Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism

item ZHAO, HONGYUN - Rice University
item YANG, LIFENG - Rice University
item BADDOUR, JOELLE - Rice University
item ACHREJA, ABHINAV - Rice University
item BERNARD, VINCENT - Md Anderson Cancer Center
item MOSS, TYLER - Md Anderson Cancer Center
item MARINI, JUAN - Children'S Nutrition Research Center (CNRC)
item TUDAWE, THAVISHA - Rice University
item SEVIOUR, ELENA - Md Anderson Cancer Center
item SAN LUCAS, F ANTHONY - Md Anderson Cancer Center
item ALVAREZ, HECTOR - Md Anderson Cancer Center
item GUPTA, SONAL - Md Anderson Cancer Center
item MAITI, SOURINDRA - Md Anderson Cancer Center
item COOPER, LAURENCE - Md Anderson Cancer Center
item PEEHL, DONNA - Stanford University
item RAM, PRAHLAD - Md Anderson Cancer Center
item MAITRA, ANIRBAN - Md Anderson Cancer Center
item NAGRATH, DEEPAK - Rice University

Submitted to: eLife
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/26/2016
Publication Date: 2/27/2016
Citation: Zhao, H., Yang, L., Baddour, J., Achreja, A., Bernard, V., Moss, T., Marini, J.C., Tudawe, T., Seviour, E.G., San Lucas, F., Alvarez, H., Gupta, S., Maiti, S.N., Cooper, L., Peehl, D., Ram, P.T., Maitra, A., Nagrath, D. 2016. Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism. eLife. 5:e10250.

Interpretive Summary: Nutrients absorbed from the diet suffer many modifications before they reach their targeted organs. Not only does these nutrients get digested to amino acids, fatty acids and simple sugars, but sometimes they get repackaged more complex forms. In this work we study how the production of exosomes (or small vesicles) by one cell type containing amino acids, lipids and small organics acids are able to feed a second cell type (tumor cells). Because exosomes are found in blood and urine of normal subjects, the process of production, circulation and utilization of exosomes has the potential to deliver needed nutrients to different tissues and organs.

Technical 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.