Abstract A060: Characterizing acinar cell and ductal cell derived PDACs in mouse models

Abstract

Abstract Understanding the origins of PDAC is critical for developing better clinical interventions. Modeling in mice has revealed that either pancreatic acinar or ductal cells can serve as the cell of origin for PDAC. Using tamoxifen-inducible Ptf1aCreER and Sox9CreER alleles to induce genetic alterations in adult pancreatic acinar and ductal cells, respectively, we showed that oncogenic Kras expression, coupled with p53 inactivation or mutation, can drive PDAC from either pancreatic cell type. PDACs derived from acinar cells resemble the classical subtype of human PDAC, while those derived from ductal cells resemble the basal-like subtype of human PDAC, suggesting that cell of origin is one factor that can influence PDAC subtype. Moreover, the histological lesions preceding cancer are notably different, suggesting that oncogenic events in each cell type result in distinct paths of tumor evolution. Such findings highlight the importance of the earliest events of tumorigenesis in influencing phenotypes and outcomes, and better understanding these different paths of PDAC evolution can therefore be critical for improving early diagnosis and treatment of PDAC. To deepen our understanding of these paths of PDAC development, we have used spatial transcriptomics to characterize the acinar and ductal cell-derived mouse PDACs, to contextualize cell-specific expression programs in cancer cell and stromal cell compartments. The segmentation of transcriptional programs by cell type is of great importance in PDAC due to a characteristically pervasive desmoplastic stroma and low neoplastic cellularity. These studies have validated differences in transcriptomic profiles of the cancer cells in these two types of PDAC, with HIF1 signaling and glycolysis pathway being upregulated in ductal cell-derived PDAC and programs that mirror tissue development and morphogenesis being more prominent in acinar cell-derived PDAC. Our analysis also revealed differences in the fibroblast and immune compartments of acinar and ductal cell-derived tumors, which we are further characterizing, and which will reveal novel strategies for tumor targeting based on the tumor microenvironment. Together, these findings suggest that these two types of PDAC are driven and sustained by distinct pathways and tumor-stromal crosstalk. To help characterize pathways central for cancer cell growth, we also generated cell lines from acinar cell and ductal cell-derived PDACs, and we are characterizing their sensitivity to different agents that modulate pathways specific to each PDAC subtype. Ultimately, this work will help to elucidate how the two major types of human PDAC develop, paving the way in finding subtype-specific vulnerabilities that may be exploited therapeutically. Citation Format: Sofia Ferreira, Brittany M. Flowers, Kathryn J. Hanson, Alberto Gatto, Sohinee Bhattacharyya, Mara H. Sherman, Laura D. Attardi. Characterizing acinar cell and ductal cell derived PDACs in mouse models [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A060.