Abstract 1265: Pan-cancer study of glycosylation-related gene expression: The emerging role of galectin-2 in tumor progression
Authors: Cocco Montana N. Manselle , Veigas Florencia , Mahmoud Yamil D. , Massaro Mora , Gatto Sabrina , Morales Rosa M. , Cagnoni Alejandro , Rabinovich Gabriel A. 
Published: June 2023

Aberrant glycosylation has emerged as an important hallmark of cancer playing a critical role in the modulation of tumor cell aggressiveness, invasiveness, and modulation of the immune and vascular programs. However, the cellular and molecular mechanisms implicated in glycan-driven cancer progression remain poorly understood.

In this study, we explored the expression profile of a glycosylation-related gene signature (Affymetrix, GlycoV4) and its association with cancer progression in tumors from different primary sites. First, we analyzed published transcriptomic data from patients’ tumor biopsies to identify pan-cancer molecular signatures associated with glycosylation-related genes including components of the glycosylation machinery and glycan-binding proteins or lectins, to determine unsupervised sample clusters with similar glyco-transcriptome profiles. Next, focusing on a melanoma transcriptomic database (TCGA-SKCM), a supervised machine learning algorithm based on Random Forest was applied to classify each biopsy according to its sample type (metastatic or primary tumor). Notably, we found that using 27 glycogenes out of the 570 included in the signature each biopsy could be classified with 87% accuracy as metastatic or primary tumor. These findings highlight the importance of components of the glycosylation machinery as novel biomarkers of tumor progression.

To explore possible mechanisms underlying glycosylation changes, we focused on the study of lectins responsible for deciphering the biological information encoded by the glycome. Particularly, galectins, a family of endogenous lectins, are known to be involved in immunomodulation, inflammation, tumor escape, and metastasis. TCGA-SKCM data was used to study the implications of two galectins expression, galectin-2 (Gal-2) mostly unexplored, and galectin-1 (Gal-1), a known regulator of antitumor immune responses. In this dataset, we found that Gal-1 expression was associated with less survival, whereas higher expression of Gal-2 was linked to increased overall survival in melanoma patients. Furthermore, initial findings revealed that Gal-2 expression was significantly augmented in metastatic biopsies whereas Gal-1 was significantly increased in primary solid tumor biopsies. Finally, to study possible mechanisms underlying these correlations, we used an immunocompetent mouse melanoma model to challenge WT and Gal-2-deficient (Lgals2-/-) mice. Interestingly, tumor volume was significantly increased in Lgals2-/- mice (p&lt;0.005) compared to their WT counterpart. To understand the molecular bases of Gal-2-driven tumor growth changes, we are studying the tumor microenvironment. Given the anti-inflammatory role of Gal-1 and the potential pro-inflammatory capacity of Gal-2, we propose that Gal-1 and Gal-2 may play opposing roles, regulating the outcome of tumor progression.

Citation Format: Montana N. Manselle Cocco, Florencia Veigas, Yamil D. Mahmoud, Mora Massaro, Sabrina Gatto, Rosa M. Morales, Alejandro Cagnoni, Gabriel A. Rabinovich. Pan-cancer study of glycosylation-related gene expression: The emerging role of galectin-2 in tumor progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1265.