HUMAN-LIKE SIALOME REMODELING LINKS HYPERGLYCEMIA TO COLORECTAL CANCER PROGRESSION

Recent research has revealed a connection between hyperglycemia and colorectal cancer (CRC) progression. This study focuses on the role of human-like sialome remodeling in this relationship. Humans lack cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH), which results in reduced synthesis of endogenous N-glycolylneuraminic acid (Neu5Gc). This change in the sialic acid composition on cell surface glycans impacts immune and metabolic processes.

The researchers investigated the diabetes-sialome-tumor axis using a CRC model that combines conditional Apc mutation with Cmah deficiency. This setup mirrors the human sialic acid repertoire. Under normal blood sugar conditions, mice with this setup had fewer polyps and smaller tumors compared to wild-type mice. They also displayed a modified tumor immune microenvironment, including more tumor-infiltrating leukocytes, more B cells, and less PD-1 expression in B cells and cytotoxic CD8+ T cells.

However, when chronic hyperglycemia was induced through low-dose streptozotocin, the results were significantly different for the genetically modified mice. Despite having the same level of hyperglycemia as the other mice, the genetically modified mice experienced more severe tumor progression, including larger tumor burden, faster lesion development, and progression to high-grade dysplasia. Histopathological analyses also showed a closer resemblance to colorectal tumors from diabetic patients.

These findings demonstrate that a human-like sialome increases susceptibility to metabolic stress and suggest that the CPC-Apc Cmah-/- mice could be a useful model for studying diabetes-associated colorectal carcinogenesis.