Tumor-Stroma Mechanics Coordinate Amino Acid Availability to Sustain Tumor Growth and Malignancy
Year: 2018
Type: article
Abstract: Dysregulation of extracellular matrix (ECM) deposition and cellular metabolism promotes tumor aggressiveness by sustaining the activity of key growth, invasion, and survival pathways. Yet mechanisms by which biophysical properties of ECM relate to metabolic processes and tumor progression remain undefined. In both cancer cells and carcinoma-associated fibroblasts (CAFs), we found that ECM stiffening mechanoactivates glycolysis and glutamine metabolism and thus coordinates non-essential amino acid flux within the tumor niche. Specifically, we demonstrate a metabolic crosstalk between CAF and cancer cells in which CAF-derived aspartate sustains cancer cell proliferation, while cancer cell-derived glutamate balances the redox state of CAFs to promote ECM remodeling. Collectively, our findings link mechanical stimuli to dysregulated tumor metabolism and thereby highlight a new metabolic network within tumors in which diverse fuel sources are used to promote growth and aggressiveness. Furthermore, this study identifies potential metabolic drug targets for therapeutic development in cancer.
Source: Cell Metabolism
Institutions: Centre National de la Recherche Scientifique, Inserm, Université Côte d'Azur, Institut de Recherche sur le Cancer et le Vieillissement de Nice, Brigham and Women's Hospital, Harvard University, Hôpital Pasteur, Institut National des Sciences Appliquées de Toulouse, Toulouse Biotechnology Institute, Bio & Chemical Engineering, MetaboHUB, Université de Toulouse, Centre Antoine Lacassagne, University of Pittsburgh, University of Pittsburgh Medical Center
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $10,400
Funders: American Heart Association, Association pour la Recherche sur le Cancer, Infrastructures en Biologie Santé et Agronomie, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Fondation pour la Recherche Médicale, Ligue Contre le Cancer, Canceropôle PACA, Canceropôle Provence-Alpes-Côte d’Azur, National Institutes of Health, National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences
Awards: G108251326, Molecular Drivers of Vascular Stiffness and Metabolic Dysfunction in HIV-Induced Pulmonary Arterial Hypertension, G2525723408, G2902957190, G3968006953, G4225708523, Regulation of pulmonary vascular cell redox state by L-2-hydroxyglutarate, G5094003450, G5191601365, G5802621812, G6188253164, G643150708, Defining the systems biology of the vascular matrix in pulmonary hypertension, Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie, Développement d'une infrastructure française distribuée pour la métabolomique dédiée à l'innovation, G8976992892, G9000037288, G9000038389, G9000072144, G9000074555, G9000084742, G9000124101, G9000195340
OpenAlex ID: W2895250239