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.

Highlights

• CMAH loss reshapes the sialome and suppresses spontaneous colorectal tumorigenesis;

• Neu5Ac-dominant glycocalyx modifies tumor-infiltrating immune cell populations;

• Hyperglycemia selectively exacerbates tumor progression in Cmah ^-/- mice;

• Diabetic Cmah ^-/- tumors shift toward high-grade dysplasia with mesenchymal expansion;

• Cmah ^-/- CPC- Apc model faithfully recapitulates diabetes-associated CRC progression in humans;

• Loss of CMAH increases susceptibility to hyperglycemia-driven colorectal cancer progression.