title: Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism.
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.
authors.affiliation: Laboratory for Systems Biology of Human Diseases, Rice University, Houston, United States.|Department of Chemical and Biomolecular Engineering, Rice University, Houston, United States.
authors.forename: Hongyun
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Laboratory for Systems Biology of Human Diseases, Rice University, Houston, United States.|Department of Chemical and Biomolecular Engineering, Rice University, Houston, United States.
authors.forename: Lifeng
authors.initials: L
authors.lastname: Yang
authors.affiliation: Laboratory for Systems Biology of Human Diseases, Rice University, Houston, United States.|Department of Chemical and Biomolecular Engineering, Rice University, Houston, United States.
authors.forename: Joelle
authors.initials: J
authors.lastname: Baddour
authors.affiliation: Laboratory for Systems Biology of Human Diseases, Rice University, Houston, United States.|Department of Chemical and Biomolecular Engineering, Rice University, Houston, United States.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Achreja
authors.affiliation: Departments of Pathology and Translational Molecular Pathology, Ahmad Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, United States.
authors.forename: Vincent
authors.initials: V
authors.lastname: Bernard
authors.affiliation: Department of Systems Biology, University of Texas, MD Anderson, Houston, United States.
authors.forename: Tyler
authors.initials: T
authors.lastname: Moss
authors.affiliation: Baylor College of Medicine, Houston, United States.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Marini
authors.affiliation: Department of Chemical and Biomolecular Engineering, Rice University, Houston, United States.
authors.forename: Thavisha
authors.initials: T
authors.lastname: Tudawe
authors.affiliation: Department of Systems Biology, University of Texas, MD Anderson, Houston, United States.
authors.forename: Elena G
authors.initials: EG
authors.lastname: Seviour
authors.affiliation: Departments of Pathology and Translational Molecular Pathology, Ahmad Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, United States.
authors.forename: F Anthony
authors.initials: FA
authors.lastname: San Lucas
authors.affiliation: Departments of Pathology and Translational Molecular Pathology, Ahmad Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, United States.
authors.forename: Hector
authors.initials: H
authors.lastname: Alvarez
authors.affiliation: Departments of Pathology and Translational Molecular Pathology, Ahmad Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, United States.
authors.forename: Sonal
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Department of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, United States.
authors.forename: Sourindra N
authors.initials: SN
authors.lastname: Maiti
authors.affiliation: Department of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, United States.
authors.forename: Laurence
authors.initials: L
authors.lastname: Cooper
authors.affiliation: Department of Urology, School of Medicine, Stanford University, Stanford, United States.
authors.forename: Donna
authors.initials: D
authors.lastname: Peehl
authors.affiliation: Department of Systems Biology, University of Texas, MD Anderson, Houston, United States.
authors.forename: Prahlad T
authors.initials: PT
authors.lastname: Ram
authors.affiliation: Departments of Pathology and Translational Molecular Pathology, Ahmad Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, United States.
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.affiliation: Laboratory for Systems Biology of Human Diseases, Rice University, Houston, United States.|Department of Chemical and Biomolecular Engineering, Rice University, Houston, United States.|Department of Bioengineering, Rice University, Houston, United States.
authors.forename: Deepak
authors.identifier: http://orcid.org/0000-0002-8999-2282
authors.initials: D
authors.lastname: Nagrath
mesh_terms: D055354:Exosomes / Q000378:metabolism; D005285:Fermentation; D005347:Fibroblasts / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis; D019344:Lactic Acid / Q000378:metabolism; D009369:Neoplasms / Q000503:physiopathology*; D010085:Oxidative Phosphorylation; D059016:Tumor Microenvironment
chemical_list: D019344:Lactic Acid; D005947:Glucose
keywords: cancer metabolism; cell biology; exosomes; human; human biology; macropinocytosis; medicine; metabolic flux analysis; reductive carboxylation; tumor microenvironment