Abstract 1528: JAG1-driven macropinocytosis as a critical regulator of nutrient scavenging and tumor progression in pancreatic cancer

Pancreatic cancer (PanCan), known for its aggressive nature, poor prognosis and often resistant to therapeutics, remains a major global health burden (Conroy, Desseigne et al. 2011, Von Hoff, Ervin et al. 2013, Howlader N 2021, Bray, Laversanne et al. 2024). Exploring new therapeutic targets is urgent. Studies have reported that PanCan cells undergo metabolic reprogramming in response to oncogenic signals for survival and tumor progression. Macropinocytosis, as an important nutrient scavenging metabolic pathway, fuels KRAS-driven PanCan cell growth, especially under nutrient-deficient condition (Ramirez, Hauser et al. 2019). The Notch signaling pathway is pivotal in PanCan initiation and development (Miyamoto, Maitra et al. 2003, Thomas, Zhang et al. 2014). Here, we demonstrated that Jagged-1 (JAG1) is the predominant Notch ligand expressed in human PanCan tissues and patient-derived xenografts, but only weakly presented in endothelial cells of normal pancreas. Elevated JAG1 gene expression is associated with worse survival in TCGA PanCan patient cohort, implicating that JAG1 is a prognostic marker for PanCan. However, whether JAG1-driven Notching signaling affects PanCan cellular metabolism remains poorly understood. Preliminary RNA-seq analysis on JAG1-depleting KPC tumor lines shows deactivated pathways activities, including “PI3k-AKT-mTOR”, “positive regulation of endocytosis” and “actin cytoskeleton organization”, all of which are important molecular events for macropinocytosis processes. We further investigated and noticed decreased dextran-TMR uptake capacities in those JAG1-depleting KPC cells, indicating attenuated macropinocytic activity upon JAG1 extinction. Along this line, the widely targeted metabolomics assay revealed peptides and amino acids as the most abundant metabolite family with significant reduction in JAG1-depleting KPC tumor cells. Finally, JAG1 ablation decreased KPC cell proliferation and spheroid forming efficiency in vitro. In addition, JAG1 deletion reduced tumor growth in syngeneic subcutaneous KPC mouse models (6419C5, 7160C2 and 6422C5) as well as in a KPC orthotopic model (6419C5). Collectively, our findings suggest JAG1 as a key driver of macropinocytosis in PanCan cells and imply the potential of JAG1 ablation to inhibit nutrient scavenging and tumor progression. Citation Format: Mofei Huang, Bingqing Zou, Yimin Ma, Wei Xin, Lan Zhou. JAG1-driven macropinocytosis as a critical regulator of nutrient scavenging and tumor progression in pancreatic cancer [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 1528.