Abstract B108: Functional Dissection of the Highly Plastic Basal Cell State in Pancreatic Cancer

Abstract Intratumoral heterogeneity in pancreatic ductal adenocarcinoma (PDAC) is characterized by the coexistence of classical epithelial, basal, and mesenchymal cancer cell states. Targeting cancer cell plasticity—the ability of tumor cells to adapt to extrinsic pressures via non-genetic mechanisms—has emerged as a promising therapeutic strategy. In parallel, the immunosuppressive tumor microenvironment remains a major barrier to effective treatment in PDAC. Yet, whether specific cell states possess distinct functional properties that drive key tumor behaviors—such as phenotypic plasticity or immune evasion—remains poorly understood. Using genetically engineered mouse models driven by oncogenic Kras G12D and loss of Trp53 (“KPC” model), we profiled primary PDAC tumors using single-cell RNA sequencing and single cell ATAC sequencing. We find that the KPC model harbors a basal state, which harbors transcriptional signature that aligns with the "basal" signature in human PDAC and is linked to poor prognosis and chemoresistance. The basal state co-expresses both epithelial and mesenchymal programs and has a distinct epigenetic landscape with accessible chromatin across gene sets that mark cancer cell states with divergent phenotypes, suggesting that this cell state is primed for cell state switching. To functionally interrogate the basal state in PDAC progression, we developed a novel lineage-tracing and ablation system. Lineage-tracing experiments revealed that the basal state has a robust capacity for differentiation into epithelial and mesenchymal states, indicating that the basal state is functionally plastic and acts as a source of fixed malignant states. Strikingly, targeted elimination of the basal state over short time periods resulted in tumor collapse, underscoring a critical role in tumor maintenance. Further, we find that the basal state is a key driver of therapeutic resistance: rather than being eliminated by treatment, it persists through phenotypic adaptation in response to both KRAS-targeted therapies and cytotoxic chemotherapy. Co-elimination of the basal state alongside these therapies leads to deeper and more durable responses, underscoring its functional role in tumor persistence under therapy. In parallel, we observe that the basal state plays a central role in enforcing immunosuppression in PDAC tumors. Basal state ablation rapidly reshapes the tumor immune microenvironment, and we observe loss of cancer-associated fibroblasts, polarization of PDAC-resident macrophages toward a pro-inflammatory phenotype, and increased infiltration of T and NK cells. Cytokine profiling of basal-ablated tumors revealed a dramatic reduction in multiple immune-modulatory and immunosuppressive cytokines. Taken together, our data indicate that PDAC harbors a striking dependency on the basal state for both therapeutic resistance and immune evasion, and encourages therapeutic approaches aimed at eradicating this critical subset of cancer cells. Citation Format: Anupriya Singhal, Kate Ryan, Samuel Rose, Hannah C. Styers, Nikhita Pasnuri, Jonathan Rub, Jung Yun Kim, Ashlyn Moore, Jill Hallin, Zeynep C. Tarcan, Olca Basturk, Rona Yaeger, James G. Christensen, Yan Yan, Elisa de Stanchina, Dana Pe'er, Tuomas Tammela. Functional Dissection of the Highly Plastic Basal Cell State in Pancreatic Cancer [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):Abstract nr B108.