Abstract PR005: The basal cell state maintains pancreatic cancers by controlling an immunosuppressive cell circuit

Abstract

Intratumoral heterogeneity is a defining feature of pancreatic ductal adenocarcinoma (PDAC), yet how distinct malignant cell states contribute to tumor behavior and stromal diversity in situ remains poorly understood. PDAC contains recurrent classical and basal states, with basal-dominant tumors associated with aggressive disease and poor outcomes. Here, we developed genetically engineered mouse models enabling state-specific lineage tracing, ablation, and gene perturbation in autochthonous PDAC to define the roles of the two dominant cell states in tumor progression. Using these systems, we find that the basal state is the dominant driver of phenotypic plasticity, tumor maintenance, and microenvironmental organization. Lineage tracing revealed that basal cells are highly plastic and generate classical and mesenchymal progeny, whereas classical cells largely retain a stable epithelial identity. Strikingly, selective ablation of the basal state, but not the classical state, induced a rapid tumor regression. Basal-cell loss triggered secondary death of malignant and stromal populations, depletion of myofibroblastic cancer-associated fibroblasts and immunosuppressive macrophages, and influx of cytotoxic lymphocytes. Spatial transcriptomics identified the classical-to-basal axis as linking malignant cell identity to coordinated stromal and immune programs within local cancer cell niches. Classical neighborhoods were epithelial-rich, whereas basal neighborhoods were enriched for myofibroblasts, suppressive macrophages, and extracellular matrix-remodeling programs. Basal-state ablation dismantled these niches, reprogrammed the cytokine milieu, and induced an ordered inflammatory response in residual classical regions, culminating in cytotoxic T- and natural killer-cell recruitment. Depletion of these effector populations blunted tumor regression, demonstrating that a cytotoxic lymphocyte response is required for tumor collapse following basal-state loss. Knockout of a single basal-derived cytokine, GM-CSF, specifically within basal cells recapitulated macrophage repolarization and lymphocyte recruitment observed upon basal state ablation and shrank tumors. These results reveal the basal cell state controls an immunosuppressive cell circuit critical for PDAC maintenance. These findings also implicate the basal cell state as the source of wound healing programs, an increasingly recognized driver of progression across diverse tumor types. Targeting the basal cell state therefore has the potential to dismantle immunosuppression, limit phenotypic plasticity, and deepen treatment responses in PDAC.