Abstract 3880: Functional dissection of the highly plastic basal cell state in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a treatment-refractory malignancy with a dismal prognosis. Targeting cancer cell plasticity—the capacity to adapt to cell-extrinsic pressure via non-genetic mechanisms—is a promising therapeutic strategy, yet cell states within PDAC harboring high plasticity remain poorly understood. Using genetically engineered mouse models driven by oncogenic KrasG12D and loss of p53 (“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 found that the basal state is highly dependent on KRAS activity, with acute KRAS inhibitor treatment leading to a selective depletion of the basal state. Taken together, our data indicates that PDAC harbors a striking dependency on the basal state and encourages therapeutic approaches aimed at eradicating this critical subset of cancer cells. Citation Format: Anupriya Singhal, Hannah Styers, Jonathan Rub, Kate Ryan, Jung Yun Kim, Zeynep C. Tarcan, Jill Hallin, Olca Basturk, Rona Yaeger, James G. Christensen, Yan Yan, Elisa de Stanchina, Tuomas Tammela. Functional dissection of the highly plastic basal cell state 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 3880.