Abstract 3512: Organ-specific effects of Smad4 in metastatic pancreatic cancer

Abstract Primary and metastatic tumors typically share the same driver gene mutations, but it is unclear if these mutations are functionally relevant across different anatomical sites. Among such mutations, inactivation of the tumor suppressor gene SMAD4 is a hallmark of pancreatic and other gastrointestinal cancers and has been associated with metastatic disease. Here, we develop a mouse model of pancreatic ductal adenocarcinoma that enables Smad4 depletion in the pre-malignant Kras-mutant pancreas and subsequent Smad4 reactivation in late-stage metastatic tumors. Whereas early Smad4 deficiency facilitated tumor formation, later Smad4 restoration had unexpected organ-specific outcomes: no effect on primary tumor growth, suppression of liver metastases, and promotion of lung metastases. Integrative multiomic analysis revealed a near-universal genomic deletion of the Cdkn2a/b locus and organ-specific changes in the tumor cells’ epigenomic state. In particular, the liver and lung differentially favored KLF vs. RUNX dominated chromatin programs, which were confirmed to underpin the divergent effects of Smad4 restoration in functional studies. Our results show how organ-dependent epigenomic changes lead to altered driver gene function in metastatic disease. This organ-specific gene-chromatin interplay may be a generalizable principle in cancer biology and invites a revised paradigm for precision oncology that considers anatomical site in the interpretation of tumor genetics. Citation Format: Kaloyan M. Tsanov, Francisco M. Barriga, Yu-Jui Ho, Direna Alonso-Curbelo, Geulah Livshits, Richard Koche, Timour Baslan, Alexandra N. Wuest, Janelle Simon, Sha Tian, Wei Luan, Scott W. Lowe. Organ-specific effects of Smad4 in metastatic pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3512.