Open AccessmTOR Repression in Response to Amino Acid Starvation Promotes ECM Degradation Through MT1‐MMP Endocytosis Arrest
Author(s) -
Colombero Cecilia,
Remy David,
AntoineBally Sandra,
Macé AnneSophie,
Monteiro Pedro,
ElKhatib Nadia,
Fournier Margot,
Dahmani Ahmed,
Montaudon Elodie,
Montagnac Guillaume,
Marangoni Elisabetta,
Chavrier Philippe
Publication year - 2021
Publication title -
advanced science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.388
H-Index - 100
ISSN - 2198-3844
DOI - 10.1002/advs.202101614
Subject(s) - microbiology and biotechnology , endocytosis , extracellular matrix , matrix metalloproteinase , pi3k/akt/mtor pathway , chemistry , psychological repression , biology , biochemistry , signal transduction , receptor , gene expression , gene
Under 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.