Galectin-2 expression in the tumor microenvironment: A silent pathway of pancreatic ductal adenocarcinoma progression

Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a complex microenvironment in which galectins play key roles. This study evaluated galectins expression to investigate its potential as a prognostic biomarker. Methods: Transcriptomic analyses were performed in silico on a cohort of 938 individuals with primary PDAC. Laser microdissection, immunohistochemistry, and RT-qPCR were used to assess the expression profile in the tumor and stromal regions of PDAC biopsies. Serum GAL-2 levels were measured by ELISA. GAL2 expression was also evaluated during distinct stages of tumor progression using the KIC murine model. Results: To analyze the galectin transcriptomic expression profile in human PDAC, transcripts of LGALS genes were evaluated in a cohort of 938 individuals diagnosed with primary PDAC tumors. LGALS2 emerged as a key transcript, exhibiting expression levels two-fold below the median in PDAC samples. Correlation analysis of LGALS transcripts revealed a positive cluster among LGALS2 , LGALS3 , LGALS4 , and LGALS9 , and a negative association between LGALS1 and LGALS2 . LGALS2 expression was downregulated in primary tumors (p = 8.76E-22) and metastatic sites (p = 2.75E-30) compared to both the control group and normal pancreatic tissue. In the KIC mouse model, a progressive reduction in LGALS2 expression was observed throughout tumor progression, from early lesions to established primary and metastatic tumors. High LGALS2 expression was associated with classical and well-differentiated epithelial PDAC subtypes, whereas low expression characterized basal-like, squamous, and mesenchymal tumors. Importantly, increased LGALS2 expression correlated with better disease-free and overall survival. Furthermore, higher LGALS2 expression was significantly associated with improved overall survival in patients treated with the FOLFIRINOX regimen (p = 4.08E-02). Additionally, low GAL-2 protein expression was observed in biopsies from patients diagnosed with PDAC. Serum GAL-2 levels were significantly lower in PDAC patients, especially those with metastasis when compared to health donors. Promoter hypomethylation (CpG island cpg25247183) was identified as a potential regulatory mechanism underlying its downregulation. Conclusions: The downregulation of LGALS2 expression across different stages of PDAC progression underscores its importance in tumor pathogenesis and suggests its potential as a prognostic and therapeutic biomarker.