Abstract 241: Clec4f is expressed in a subset of PDAC metaplastic neuroendocrine cells and alters tumor cell growth
Authors: Bailey A. Bye, R. McKinnon Walsh, Austin E. Eades, Kathleen E. DelGiorno, Michael N. VanSaun
Journal: Cancer Research (2025)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with a 5-year survival rate of just 13%. Poor survival is due in part to late detection, as well as resistance to current standard-of-care therapeutics. PDAC tumorigenesis is a result of exocrine cell metaplasia: when stressed, acinar cells transdifferentiate to form metaplastic ducts in a process called acinar-to-ductal metaplasia (ADM). ADM is normally protective, but if metaplastic ductal cells develop a mutation in the proto-oncogene Kras, they can become trapped in the transdifferentiated state and form neoplastic lesions (PanINs), which can eventually develop into PDAC. Metaplastic ducts contain a myriad of cell types, including metaplastic neuroendocrine cells, which have been shown to promote neoplastic growth and PDAC tumorigenesis. In a subset of metaplastic neuroendocrine cells, we have identified upregulation of carbohydrate receptor Clec4f. In humans, Clec4f is upregulated in PDAC tumors compared to normal pancreas and correlates with poor prognosis when elevated in early stage disease. While Clec4f’s function in mice has been primarily associated with glycan recognition for antigen clearance by mouse liver macrophages, its function in PDAC tumor cells is unknown. Since we have identified Clec4f expression in a discrete subpopulation of pancreatic epithelial cells associated with early stage disease, we hypothesize that Clec4f plays a novel role in regulating PDAC tumorigenesis in response to binding glycans in the tumor microenvironment. Ectopic overexpression of Clec4f (Clec4f-oe) in murine PDAC cells revealed prominent reduction of classically mitogenic pathways including MAPK (via phosphorylated ERK) and PI3K (via phosphorylated AKT) as well as elevated levels of phosphorylated c-Myc (S62), which has been shown to play a role in regulating ductal-to-neuroendocrine lineage plasticity and therapeutic resistance. Clec4f-oe also preliminarily protected PDAC tumor cells from cell death via Gemcitabine or a D-galactose-based senescence model. In accordance with other studies in macrophages, Clec4f expression in PDAC tumor cells appears to be niche dependent. We found that, in Clec4f-oe tumor cells, incubation with galactose stabilizes Clec4f expression and Clec4f-associated signaling alterations. These data suggest that carbohydrate binding by Clec4f alters growth and plasticity phenotypes in PDAC tumor cells. Future experiments will investigate the intracellular binding partners for Clec4f to interrogate its signaling function in metaplastic neuroendocrine cells in early PDAC. Citation Format: Bailey A. Bye, R. McKinnon Walsh, Austin E. Eades, Kathleen E. DelGiorno, Michael N. VanSaun. Clec4f is expressed in a subset of PDAC metaplastic neuroendocrine cells and alters tumor cell growth [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 241.