GLUT1/SGLT1 balance associates with high-glucose buffering of metformin-induced lysosomal deacidification and mTORC1 inhibition in colorectal cancer
Abstract
Metformin has anticancer potential, but benefit in colorectal cancer (CRC) is heterogeneous and determinants of tumor cell response remain unclear. We tested whether extracellular glucose and the relative expression of glucose transporter 1 (GLUT1/SLC2A1) and sodium-glucose cotransporter 1 (SGLT1/SLC5A1), quantified as a glucose transporter ratio score (GTRS), are associated with buffering of metformin effects. We combined a 1,2-dimethylhydrazine (DMH)-induced CRC model, glucose-controlled cell-line experiments, and analyses of public bulk, single-cell, and spatial transcriptomic datasets. In mice, metformin (200 mg/kg/day) reduced DMH-associated neoplastic progression and Cyclin D1 expression. In vitro, metformin (5 mM) reduced viability and clonogenic growth while reducing endolysosomal acidity and inhibiting mTORC1 downstream signaling under normal glucose. Metformin-induced changes were attenuated under high glucose. Buffering of lysosomal acidity loss was stronger in the GTRS-high HCT116 cells than in the GTRS-low HT29 cells, with partial rescue of growth readouts in both lines. In human single-cell datasets, high-GTRS malignant clusters showed higher lysosome-related transcriptional program scores. In spatial transcriptomic datasets, lysosome-related programs were enriched at the tumor-stroma interface, where stromal laminin ligands and epithelial integrin receptors showed enriched spatial co-localization. In human bulk cohorts, higher GTRS was enriched in the…
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