mTOR Repression in Response to Amino Acid Starvation Promotes ECM Degradation Through MT1‐MMP Endocytosis Arrest

• DOI: 10.1002/advs.202101614
• Publication Date: 2021-07-12T05:31:50Z
• Authors: Cecilia Colombero; David Remy; Sandra Antoine‐Bally; Anne‐Sophie Macé; Pedro Monteiro; Nadia ElKhatib; Margot Fournier; Ahmed Dahmani; Elodie Montaudon; Guillaume Montagnac; Elisabetta Marangoni; Philippe Chavrier
• Keywords: 0301 basic medicine; clathrin‐mediated endocytosis; [SDV]Life Sciences [q-bio]; extracellular matrix; Science; Breast Neoplasms; MT1‐MMP; Mice; 03 medical and health sciences; breast cancer; Cell Line, Tumor; Matrix Metalloproteinase 14; Animals; Humans; Amino Acids; Research Articles; invadopodia; 2. Zero hunger; 0303 health sciences; TOR Serine-Threonine Kinases; Q; Endocytosis; Extracellular Matrix; [SDV] Life Sciences [q-bio]; mTOR; Female

AbstractUnder conditions of starvation, normal and tumor epithelial cells can rewire their metabolism toward the consumption of extracellular proteins, including extracellular matrix‐derived components as nutrient sources. The mechanism of pericellular matrix degradation by starved cells has been largely overlooked. Here it is shown that matrix degradation by breast and pancreatic tumor cells and patient‐derived xenograft explants increases by one order of magnitude upon amino acid and growth factor deprivation. In addition, it is found that collagenolysis requires the invadopodia components, TKS5, and the transmembrane metalloproteinase, MT1‐MMP, which are key to the tumor invasion program. Increased collagenolysis is controlled by mTOR repression upon nutrient depletion or pharmacological inhibition by rapamycin. The results reveal that starvation hampers clathrin‐mediated endocytosis, resulting in MT1‐MMP accumulation in arrested clathrin‐coated pits. The study uncovers a new mechanism whereby mTOR repression in starved cells leads to the repurposing of abundant plasma membrane clathrin‐coated pits into robust ECM‐degradative assemblies.