Abstract A016: Defining UHRF1 as a crucial factor in pancreatic cancer progression and treatment

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant disease with a dismal survival rate due to insufficient early diagnosis markers and effective treatment options. The initiation and progression of this disease have been well characterized as a multistep process associated with genetic and epigenetic changes within malignant cells. Here, we focus on UHRF1 (ubiquitin-like with plant homeodomain and ring finger domains 1), a multidomain protein pivotal for maintaining DNA methylation that is known to be overexpressed in PDAC. This overexpression has been implicated in the epigenetic silencing of multiple tumor suppressor genes in pancreatic cancer, thereby playing a significant role in pancreatic oncogenesis. Although previous studies have elucidated UHRF1’s role in pancreatic tumorigenesis, the therapeutic potential of targeting UHRF1 remains unknown. To address this gap, we generated pancreatic-specific Uhrf1 knockout mice combined with KRASG12D expression (KC-Uhrf1 PKO) to investigate the impact of UHRF1 loss-of-function on PDAC development and progression. Compared to KC mice, KC-Uhrf1 PKO mice exhibited a reduction in precursor lesion formation, which is accompanied by increased CD8+ T cells, decreased fibrosis, and a curious replacement of exocrine tissue with adipocytes. Generation of Uhrf1 PKO mice revealed that pancreatic lipomatosis and increased immune infiltration stem from UHRF1 dysregulation alone. The protective effect from UHRF1 ablation is further exemplified in a survival model combining oncogenic Kras expression with p53 loss of heterozygosity. Collectively, this data suggests that UHRF1 mediates vital reprogramming for PDAC tumorigenesis and highlights UHRF1 as a promising therapeutic avenue. Citation Format: Austin D. Silva, Sabrina E. Calderon, Avary S. Baker, Mariam Mohagheghi, Rima Singh, Taryn Morningstar, Cecily Anaraki, Christopher J. Halbrook. Defining UHRF1 as a crucial factor in pancreatic cancer progression and treatment 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 (8Suppl₁): Abstract nr A016.