HUMAN-LIKE SIALOME REMODELING LINKS HYPERGLYCEMIA TO COLORECTAL CANCER PROGRESSION

Authors

Santos, R. C. M., Ferreira, G. S., Lopes, A. L., Silva, V. H. N., Fonseca, A. C., Fontes, M., Bastos, C. d. S., Takiya, C. M., Machado, J. C., Werneck, M. B. F., Dias, W. B., Alisson-Silva, F., Todeschini, A. R.

Abstract

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.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 10 Sep 2026.

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