Nicolazzi, G. | Search bioRxiv

bioRxiv2026

Galectin-8 Modulates Membrane CD44v Localization and Tempers STAT3 Signaling in Gastric Metaplasia

ABSTACTGalectin-8 is a lectin that binds N-acetyllactosamine moieties with preference towards those with acidic, terminal modifications (-O-sialyated, 3-O-sulfated). As CD44-variants (CD44v) are biomarkers of metaplasia and cancer, a hyaluronic acid receptor that modulates STAT3 signaling, and specifically expresses 3-Sialyl-LeA/X glycotopes, we asked whether galectin-8 might play a role in gastric metaplasia. Using a synchronous, chemically induced murine model that produces gastric spasmolytic polypeptide expressing metaplasia (SPEM), we compared Lgals8-/- mice to congenic wild-type C57BL/6J mice. We found that galectin-8 was necessary for membrane localization of CD44v on SPEM cells at the base of the glands, suggesting a physical interaction between galectin-8 and CD44v. Metaplastic glands from Lgals8-/- mice had an increase in nuclear pSTAT3 compared to C57BL/6J mice, suggesting that galectin-8 restrains CD44 -> STAT3 signaling. This effect was more prominent in the neck compared to the base, which has greater abundance of CD44v after injury in Lgals8-/- mice. Derepression of STAT3 signaling may explain why low galectin-8 levels is associated with a worse prognosis in gastric cancer.

cancer biology↗

bioRxiv2026

Galectin-3 is Necessary for Selective Cathartocytosis, which Expedites the Development of Proliferative Gastric SPEM

The expression and secretion of sulfated colonic-type mucins is a feature of high-risk metaplasias of the gastrointestinal foregut (Barretts esophagus, type III intestinal metaplasia of the stomach, and pancreatic intraepithelial neoplasia). Galectin-3 is a lectin that preferentially associates with galactose modified by a 3-O-sulfate relative to its unmodified counterparts and is upregulated as the tissue transitions to high-risk metaplasia, dysplasia, and cancer. Since both galectin-3 and sulfated glycotopes are aberrantly and concurrently overexpressed in high-risk premalignant and malignant tissue transformations, we sought to investigate the role of galectin-3 in the metaplastic reaction. We found that injury induces the expression of Lgals3 at the RNA and protein levels. Unlike cancer cell lines, we show that in vivo galectin-3 colocalized with sulfomucins in zymogenic granules of the gastric chief cell. Utilizing a synchronous, chemically-induced murine model that produces spasmolytic polypeptide expressing metaplasia, we found that galectin-3 facilitates cathartocytosis of the vesicles it resides in, but not organelles lacking LGALS3. Inhibition of cellular downscaling resulted in delayed expression of the metaplastic transcription factor Sox9 as well as proliferation. Here, we present a new role for galectin-3 in promoting the transition from normal, homeostatic tissue to metaplasia and our data suggest that cathartocytosis represents an unconventional secretory pathway for galectin-3, which has been a matter of controversy as galectins are not secreted via canonical pathways.

cancer biology↗