Abstract 761: Shared and heterogeneous structural and transcriptional signatures of pre-cancerous cystic lesions in the development of PDAC

Abstract Pancreatic ductal adenocarcinoma PDAC has been observed to arise in the context of diverse pre-cancerous cystic (intraductal papillary mucinous neoplasms (IPMN) and mucinous cystic neoplasms (MCNs)) and pre-cystic (pancreatic intraepithelial neoplasia (PanIN)) lesions in the clinic. While mouse models of PDAC and these precancerous lesions have existed for a decade, only recently has the transcriptional signature of dysplastic progression for one of these lesions (PanIN) been thoroughly characterized at single cell resolution. Utilizing a multimodal, spatial interrogation via Xenium and co-detection by indexing (CODEX) of PanIN (n=5), IPMNs (n=5), MCNs (n=2), and PDAC (n=5) at varying stages, we identify transcriptional signatures of each lesion at varying stages of progression and alterations of the pre-cancer microenvironment composition and structure. In doing so, we observed a conserved gastric metaplasia phenotype along the progression from PanIN to IPMN that is maintained in a subset of cells in higher grade and dual-subtype IPMNs. This phenotype is diminished in invasive PDAC. By contrast, MCN cyst epithelium and a small subset of PanIN cells lacked the expression of gastric markers and exhibited a more reactive ductal phenotype. Directly, adjacent to each of the pre-cancerous lesions we observed a thin layer of myCAF-like fibroblasts frequently interspersed with T cells that were otherwise excluded from the region surrounding invasive PDAC while the myCAF layer expanded. In the case of MCNs specifically this thin myCAF-like layer coincided with an ovarian-like expression signature alongside other markers. Our findings offer a high resolution window into the heterogeneity of PDAC precursor lesions, highlighting shared dysplastic expression and structural phenotypes along the progression towards invasive PDAC. Citation Format: Austin N. Southard-Smith, Reyka G. Jayasinghe, Andre L. Targino da Costa, Liang-I Kang, John M. Herndon, Jacqueline Mudd, Andrew Houston, Xiang Li, Michael C. Wendl, Faria A. Simin, Xiangwei Fang, Feng Chen, Koushik K. Das, Ryan C. Fields, Li Ding. Shared and heterogeneous structural and transcriptional signatures of pre-cancerous cystic lesions in the development of PDAC [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 761.