Abstract 2641: Glycosyltransferases at the helm of organ specific metastasis of pancreatic ductal adenocarcinoma

Abstract Background: Pancreatic cancer (PC) deaths, incident cases, and disability-adjusted life-years globally have more than doubled from 1990 to 2017 with five-year survival rate of less than 14%, a trend likely to persist with population aging. The most common cause of mortality in pancreatic cancer patients is the metastasis of neoplastic cells to vital organs like the lungs and liver, and patients develop an inoperable condition due to late diagnosis. Malignant transformation of cancer cells is associated mainly with altered tumor-cell glycosylation at the cell surface. The expression of glycosyltransferases (GTs) is instrumental in modulating the cellular phenotype and promoting cancer cell survival at the metastatic niche. Specifically, we found that upregulation of (glucosaminyl (N-acetyl) transferase 3) GCNT3 and (beta-1, 3-N-acetylglucosaminyltransferase 3) B3GNT3 expression are key mediators in altering glycosylation patterns in PC cells and enhancing the metastatic proclivity towards the liver and lung, respectively. Methodology: We utilized two different metastatic models to replicate key aspects necessary to study the lung and liver-specific metastasis of PC. The RT2 PCR array was used to analyze the global gene expression of GTs between primary PC cells and lung/liver metastatic models. Further, qPCR, ddPCR, and western blot techniques were used to confirm the differential expression of GTs at RNA and protein levels. Immunohistochemistry and Immunofluorescence experiments on the matched human primary and metastatic PC tissues validated the higher expression of specific GTs in the metastatic PC tissues when compared to the primary tumor. Results: An unbiased transcriptional screen revealed a reciprocal >2-fold increase in GCNT3 and B3GNT3 expression in the liver and lung metastatic cell lines, respectively. Further, qPCR, dd-PCR, and western blot results confirmed the same expression pattern in liver and lung-specific metastatic cells compared to the PC controls. These results were further validated in human tissue from the same patient's primary pancreatic tumor and metastatic lung and liver tissues collected through the UNMC Rapid Autopsy program (UNMC-RAP). Conclusion: Our data suggest that a clonal population of PC cells that highly express GCNT3 and B3GNT3 plays a pivotal role in reshaping glycosylation profiles, thereby augmenting their tendency for liver and lung-specific metastasis, respectively. This study highlights the critical correlation between glycosylation and organ-specific metastasis in PC. Citation Format: Venkatesh Varadharaj, Frank Leon, Nivedeta Krishna Kumar, Palanisamy Nallasamy, Wyatt D. Petersen, Zahraa Wajih I. Alsafwani, Annant Bir Kaur, Kirtana Arikath, Sanchita Rauth, Saravanakumar Marimuthu, Surinder K. Batra, Moorthy P. Ponnusamy. Glycosyltransferases at the helm of organ specific metastasis of pancreatic ductal adenocarcinoma [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 2641.