Abstract 4130: Targeting epigenetically-driven inflammation for PDAC metastasis prevention in high-risk individuals

Abstract

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a dire prognosis, in large part due to the late stage at which it is diagnosed in most patients. High-risk individuals (HRIs) identified through family history or germline genetic testing are candidates for imaging-based screening, yet even with intensive surveillance, metastasis often occurs between scans. Our study aims to address this critical clinical challenge by investigating the epigenetic determinants of PDAC metastasis and developing novel strategies for metastasis prevention in HRIs. Methods: Innovative transplantation models of PDAC liver and peritoneal metastasis incorporating DNA barcodes for subclonal tracking were developed to facilitate the identification of subclones with high or low metastatic potential. An in-depth epigenomic characterization and comparison of these subclones was performed utilizing assay for transposase-accessible chromatin with sequencing (ATAC-seq) and RNA-seq. Results: Metastasis-high subclones demonstrate widespread chromatin accessibility differences relative to their metastasis-low peers. These differences are linked to expression changes for genes involved in motility, differentiation, survival, and particularly inflammation. Top epigenetically activated genes in metastasis-high subclones include the pro-inflammatory cytokines IL-1α and IL-23α and the pro-inflammatory cytokine receptor IL-18R1. Discussion: These findings highlight the role of epigenetic changes in PDAC metastasis, especially activation of inflammatory pathways resulting from altered chromatin accessibility. These insights provide a foundation for exploring anti-inflammatory agents for PDAC metastasis prevention. Targeting inflammation, alongside imaging-based screening, could significantly improve outcomes for HRIs. Citation Format: Jesse Handler, Reza Kalhor. Targeting epigenetically-driven inflammation for PDAC metastasis prevention in high-risk individuals [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4130.