Abstract A026: Hereditary chronic pancreatitis induced plasticity cooperates with mutant Kras in early pancreatic carcinogenesis

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal cancer with hereditary chronic pancreatitis (CP) conferring a significantly increased risk. Hereditary CP is caused by mutations in genes, such as PRSS1, SPINK1, CTRC, or CPA1 and presents with variable onset. However, the underlying mechanisms through which CP contributes to oncogenic transformation remain poorly understood. To elucidate this, we generated a genetically engineered mouse model carrying CP-associated human p.N256K carboxypeptidase A1 (CPA1) mutation and oncogenic Kras mutation resulting in Ptf1a Cre ;Kras LSL-G12D ;Cpa1 N256K (KC-Cpa1) mouse strain. Histological analyses of the KC-Cpa1 pancreas revealed accelerated development of early steps of PDAC including acinar-to-ductal metaplasia (ADM), pancreatic intraepithelial neoplasia (PanIN) lesions, and extensive fibrosis. Ex vivo 3D acinar cultures from 8-week-old KC-Cpa1 mice pancreata demonstrated enhanced ADM formation compared to Ptf1a Cre (Cre), Cpa1 N256K/N256K (Cpa1), and Ptf1a Cre ;Kras LSL-G12D (KC). These findings suggest that inflammation induced by the Cpa1 N256K mutation synergizes with oncogenic Kras mutation to promote the early initiation of PDAC. To explore the cellular heterogeneity and transcriptional program of metaplastic cells, we performed single cell RNA sequencing of pancreata of KC-Cpa1, KC, Cpa1, and Cre which revealed Cpa1 N256K -induced exocrine plasticity marked by an early ADM state and inflammatory phenotype of ductal cells (iDucts). Furthermore, single cell RNA sequencing also suggested disease-specific signaling between ductal cells, granulocytes, and fibroblasts. These results support the utility of KC-Cpa1 mouse model for studying early stages of CP-induced PDAC. Citation Format: Tanvi V. Inamdar, Ferdinand Krannich, Nico Hesselbarth, Atul Verma, Teresa Vauti, Ghanem El Kassem, Jasmine Hillmer, Michael Boettcher, Ivonne Regel, Heidi Griesmann, Irene Esposito, Markus Glaß, Monika Hämmerle, Patrick Michl, Helmut Laumen, Jonas Rosendahl. Hereditary chronic pancreatitis induced plasticity cooperates with mutant Kras in early pancreatic carcinogenesis [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): nr A026.