Extracellular matrix remodeling regulates glucose metabolism through TXNIP destabilization

The metabolic state of a cell is influenced by cell-extrinsic factors, including nutrient availability and growth factor signaling. Here, we present extracellular matrix (ECM) remodeling as another fundamental node of cell-extrinsic metabolic regulation. Unbiased analysis of glycolytic drivers identified the hyaluronan-mediated motility receptor as among the most highly correlated with glycolysis in cancer. Confirming a mechanistic link between the ECM glycosaminoglycan hyaluronan and metabolism, treatment of both cells and xenograft tumors with hyaluronidase (HAase) triggers a robust increase in glycolysis. This is largely achieved through rapid receptor tyrosine kinase-mediated induction of mRNA decay factor ZFP36, which targets TXNIP transcripts for degradation. Since TXNIP promotes internalization of the glucose transporter GLUT1, its acute decline enriches GLUT1 at the plasma membrane. Functionally, induction of glycolysis by HAase is required for concomitant acceleration of cell migration. This interconnection between ECM remodeling and metabolism is exhibited in dynamic tissues states including tumorigenesis and embryogenesis.

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