Abstract 86: The role of truncated O-glycans in PDAC progression: Linking C1GALT1 loss to metabolic alterations

Abstract Pancreatic cancer (PC) remains one of the leading causes of cancer death, often advancing undetected until late stages. Aberrant O-glycosylation, including the expression of truncated carbohydrate antigens such as Tn and STn, is a hallmark of PC; however, the mechanisms linking these glycan alterations to tumor progression and metastasis are poorly understood. This study investigates the role of truncated O-glycans, driven by the loss of the O-glycosyltransferase core 1 synthase (C1GALT1), in promoting metabolic reprogramming and early metastatic dissemination in pancreatic cancer. C1GALT1 catalyzes the biosynthesis of mucin-type O-glycans, but its inactivity in PC leads to the accumulation of truncated glycans. Analysis of poorly differentiated human PC tissues revealed a significant loss of C1GALT1 expression. CRISPR/Cas9-mediated knockout (KO) of C1GALT1 in PC cell lines also results in increased Tn and STn glycan expression, enhanced tumorigenic potential, and increased metastatic capacity. Using genetically engineered mouse models (C1galt1 KO with KrasG12D/Trp53R172H/+ mutations), we observed early-onset and widespread metastasis, mirroring the heightened aggressiveness associated with C1GALT1 loss in pancreatic cancer. Transcriptomic profiling through RNA sequencing and pathway enrichment analysis in C1GALT1 KO PC cells revealed significant upregulation of cholesterol metabolism pathways, suggesting that the loss of C1GALT1 may drive metabolic changes to support the aggressive behavior of PC cells. Supporting this, functional assays demonstrate a significant increase in wound healing and migratory capacity of C1GALT1 KO cells compared to control PC cells, highlighting their enhanced motility and potential for metastasis. These findings underscore the role of C1GALT1 loss in driving aggressive tumor phenotypes, potentially through metabolic and functional adaptations that promote the need for further investigation. This work highlights a previously underexplored link between aberrant glycosylation and metabolic rewiring in pancreatic cancer. By elucidating the role of C1GALT1 loss in driving these processes, our findings provide novel insights into the mechanisms of tumor progression and identify potential vulnerabilities for therapeutic intervention. Targeting the interplay between glycosylation and metabolic pathways offers a promising avenue to disrupt the aggressive phenotype of pancreatic cancer. Citation Format: Wyatt Petersen, Venkatesh Varadharaj, Zahraa I. Alsafwani, Surinder K. Batra, Moorthy P. Ponnusamy. The role of truncated O-glycans in PDAC progression: Linking C1GALT1 loss to metabolic alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 86.