Matched pancreatic cancer liver metastatic model system reveals cancer cell-dependent organotropism and site-specific tumor microenvironment reflective of human disease
Background: Pancreatic ductal adenocarcinoma (PDAC) mortality is driven largely by liver metastatic disease; however, the malignant cell states and tumor microenvironmental features of PDAC liver metastases remain obscure. Methods: We developed a transplant model system of matched pancreatic and liver tumors to study PDAC metastatic progression. Using this model, we identified murine PDAC cell lines with distinct liver metastatic capacities and performed multiomic profiling of matched primary pancreatic and metastatic liver tumors. Transcriptional programs associated with high and low liver tropism were defined and evaluated across tumor models and independent human PDAC datasets. Spatial and tumor-immune interaction analyses were used to characterize microenvironmental niches, immune composition, and cellular relationships within primary and metastatic tumors. Results: A high-liver-tropic transcriptional program was enriched in high liver-tropic cell lines and malignant cells within liver metastases, conserved across human PDAC datasets, and associated with inferior patient survival. High- and low-liver-tropic tumor states occupied distinct liver microenvironmental niches and exhibited different tumor-immune communication networks, accompanied by local and systemic changes in immune composition. Liver metastases also displayed features of enhanced immunosuppression, including increased proximity of CD4+ and CD8+ T cells to tumor cells and greater spatial association between regulatory T cells and exhausted CD8+ T cells. Conclusions: These findings identify conserved PDAC cell states associated with differential liver metastatic capacity and demonstrate that liver metastasis is accompanied by spatial and immunologic remodeling of the tumor microenvironment. Together, the study provides a framework for understanding how tumor-intrinsic metastatic programs interact with site-specific immune ecosystems in PDAC.