Abstract A048: Robust Pancreatic Cancer Liver Metastatic Model System Reveals Cancer Cell Dependent Organotropism and Site-specific Tumor Microenvironment Regulation

Abstract

Metastatic pancreatic adenocarcinoma is the dominant clinical presentation with a grim 3% 5-year survival rate. Over 80% of metastatic disease occurs in the liver and has the poorest outcomes. Overall, there is little mechanistic understanding of what promotes liver metastatic outgrowth and organotropism. Our recent work using spatial transcriptomics on unique matched primary tumors and metastases revealed distinct cellular ecosystems, noting reduced desmoplasia, high proliferation, spatially constrained metabolism, and heightened pro-tumorigenic myeloid infiltration and T-cell dysfunction at the invasive border of liver metastases. However, moving beyond these observations requires establishing causal links between molecular drivers and metastatic competence. Causal studies are limited by current model systems, the spontaneous genetically engineered mouse models (GEMM) that form the basis of pre-clinical studies do not sufficiently model the clinical metastatic reality with robust matched pancreas and liver tumors, and are further hampered with inconsistent metastatic rates and unpredictable progression for timed analysis. Syngeneic transplants of GEMM-derived cancer lines into wild-type mice provide a rapid pre-clinical model system of liver disease. However, the liver-metastatic rates varies between cell lines, even with identical driving mutations. We suspected that the unexplored mechanisms driving these differences in metastatic outgrowth present an opportunity to understand critical biology. Here we report the development a consistent model system of matched pancreatic and liver tumors using syngeneic cell lines with high and low tropism for liver metastatic outgrowth in C57Bl/6 mice. These lines are transplanted at low cell numbers to better allow the evolution of the site-specific tumor microenvironment and provide a reliable model system to examine both cancer-cell intrinsic and site-specific microenvironmental factors dictating liver outgrowth. Our observations of comparable pancreatic growth, successful metastatic growth in other organs (peritoneum or lung), and micro-metastatic lesions in the liver at early time points, suggests the liver-tropic differences fall within the ability of these cells to successfully outgrow in the liver microenvironment, rather than in vivo proliferative or extravasation differences. Comparison of gene expression between high and low liver-tropic cell lines identified several immune regulatory genes and a general increase in lipid metabolism, consistent with our published patient data. Finally, spatial quantifications of these lesions using a novel 46-plex murine immunotyping panel on FFPE tissues show similar suppressive immune cells at the interface of the tumor and normal liver as observed in our patient data, but evolves across differing lesion size, suggestive of a spatiotemporal progression. Altogether, this model system provides a robust, efficient pre-clinical platform to dissect spatiotemporal drivers of liver metastatic disease. Citation Format: Christina R. Larson, Jace Baines, Ayushi Mandloi, Meet Patel, Tuan Tran, Nailah Jones, Ateeq M. Khaliq, Christopher A. Risley, Robert S. Welner, Satwik Acharyya, Julienne L. Carstens. Robust Pancreatic Cancer Liver Metastatic Model System Reveals Cancer Cell Dependent Organotropism and Site-specific Tumor Microenvironment Regulation [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3): nr A048.