CMTM6 mediates the Warburg effect and promotes the liver metastasis of colorectal cancer

Abstract

Liver metastasis of colorectal cancer (CRC) is a leading cause of death among cancer patients. The overexpression of glucose transporter 1 (Glut1) and enhanced glucose uptake that are associated with the Warburg effect are frequently observed in CRC liver metastases, but the underlying mechanisms remain poorly understood. CKLF-like MARVEL transmembrane domain-containing protein 6 (CMTM6) regulates the intracellular trafficking of programmed death-ligand-1 (PD-L1); therefore, we investigated whether CMTM6 regulates Glut1 trafficking and the Warburg effect in CRC cells. We found that knocking down of CMTM6 by shRNA induced the lysosomal degradation of Glut1, decreased glucose uptake and glycolysis in CRC cells, and suppressed subcutaneous CRC growth in nude mice and liver metastasis in C57BL/6 mice. Mechanistically, CMTM6 forms a complex with Glut1 and Rab11 in the endosomes of CRC cells, and this complex is required for the Rab11-dependent transport of Glut1 to the plasma membrane and for the protection of Glut1 from lysosomal degradation. Multiomics revealed global transcriptomic changes in CMTM6-knockdown CRC cells that affected the transcriptomes of adjacent cancer-associated fibroblasts from CRC liver metastases. As a result of these transcriptomic changes, CMTM6-knockdown CRC cells exhibited a defect in the G2-to-M phase transition, reduced secretion of 60 cytokines/chemokines, and inability to recruit cancer-associated fibroblasts to support an immunosuppressive CRC liver metastasis microenvironment. Analysis of TCGA data confirmed that CMTM6 expression was increased in CRC patients and that elevated CMTM6 expression was associated with worse patient survival. Together, our data suggest that CMTM6 plays multiple roles in regulating the Warburg effect, transcriptome, and liver metastasis of CRC. Liver metastasis in colorectal cancer patients increases death rates, with current treatments often inadequate due to a lack of understanding of the underlying processes. This study explores how CRC cells change their metabolism to survive in the liver, focusing on the Warburg effect, where cancer cells use glycolysis preferentially. It focuses on the role of a protein called CMTM6 in this metabolic change. The researchers performed experiments on human and mouse CRC cells and used both in vitro and in vivo models, including mice with and without immune systems, to study the effects of CMTM6 on CRC growth and liver metastasis. The results showed reducing CMTM6 levels led to decreased glycolysis of CRC cells, CRC tumor growth and liver metastasis in mice. Future studies could lead to more effective treatments for CRC patients with liver metastases. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.