Abstract 2741: Novel murine models of epigenetic dysregulation in SWI/SNF-mutated cholangiocarcinoma

Abstract SWI/SNF chromatin remodeling complexes are frequently mutated across human cancers, including cholangiocarcinoma (CCA). Dysregulation of this complex due to loss of function mutations in AT-rich interaction domain-1A (ARID1A) and polybromo-1 (PBRM1) occur in up to 18% and 10% of cases respectively. SWI/SNF subunit mutations frequently co-occur alongside PI3K/AKT pathway activation. Preexisting literature suggests altered gene expression and protein synthesis contribute to CCA oncogenesis, but our understanding of these mechanisms remains immature. Genetically accurate preclinical models are needed to define the roles of ARID1A and PBRM1 in CCA and identify therapeutic targets. We developed novel murine models of CCA with either ARID1A, PBRM1 or dual ARID1A/PBRM1 (APAC) knockout in the context of AKT activation, utilizing a surgical biliary transfection method for somatic gene editing with CRISPR/Cas9. Within 8 months, mice formed numerous liver tumors, predominantly CCA and mixed CCA/HCC. Knockout of ARID1A and PBRM1 was confirmed through genomic PCR, qRT-PCR, and immunoblot assays. Histologically, murine APAC tumors displayed phenotypic similarities to human CCA, including dense cancer-associated fibroblast infiltration and variable CD45+ immune cell infiltration. A novel, syngeneic CCA cell line was isolated from a dual ARID1A/PBRM1 knockout tumor (APAC-2). RNA-sequencing of primary tumors and the APAC-2 cell line versus a non-invasive cholangiocyte cell line with AKT activation only (AC), was performed to identify differentially expressed genes (DEGs) of interest in ARID1A and PBRM1-deficient CCA. Periostin (Postn) was among the top upregulated genes in the APAC-2 cell line. POSTN is a secreted glycoprotein that is upregulated in human CCA and may be therapeutically targetable. Knockdown of periostin inhibited the in vitro growth of APAC-2 cells and a human CCA cell line with ARID1A mutation and periostin overexpression (HuH-28). These studies serve to characterize and validate a genetically relevant murine model of epigenetic dysregulation in ARID1A and PBRM1-deficient CCA. This model can be used for identification and validation of potential drug targets. Ongoing work focuses on studying multiple dysregulated pathways and testing dependence on genes of interest, including periostin, as potential treatment strategies for CCA. Citation Format: Jayla Millender, Jennifer Tomlinson, Ryan Watkins, Danielle Carlson, Jack Sample, Nathan Werneburg, Rory Smoot, Keith Robertson, Gregory Gores, Caitlin Conboy. Novel murine models of epigenetic dysregulation in SWI/SNF-mutated cholangiocarcinoma [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 2741.