HUMAN-LIKE SIALOME REMODELING LINKS HYPERGLYCEMIA TO COLORECTAL CANCER PROGRESSION
The evolutionary loss of cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH) abolished endogenous N-glycolylneuraminic acid (Neu5Gc) synthesis in humans, reshaping the sialic acid at the cell surface glycans and influencing immune and metabolic processes. However, whether a human-like sialome modulates the impact of metabolic stress on colorectal cancer (CRC) progression remains unclear. Here, we investigated the diabetes-sialome-tumor axis using a spontaneous CRC model combining conditional Apc mutation with Cmah deficiency, thereby recapitulating the human sialic acid repertoire. Under euglycemic conditions, CPC-Apc Cmah-/- mice exhibited reduced polyp numbers and tumor burden compared with WT mice, accompanied by remodeling of the tumor immune microenvironment, including increased tumor-infiltrating leukocytes, enrichment of B cells, and reduced PD-1 expression in B cells and cytotoxic CD8+ T cells. Induction of chronic hyperglycemia with low-dose streptozotocin revealed a striking genotype-specific effect. Despite comparable hyperglycemia between genotypes, tumor progression was dramatically exacerbated exclusively in Cmah-/- mice, with increased tumor burden, accelerated lesion development, and progression toward high-grade dysplasia. Histopathological analyses further revealed increased mesenchymal expansion and close resemblance to colorectal tumors from diabetic patients. Together, these findings demonstrate that a human-like sialome increases susceptibility to metabolic stress and identify CPC-Apc Cmah-/- mice as a translationally relevant model for investigating diabetes-associated colorectal carcinogenesis.