Abstract 121: A genetic signature of cancer dormancy: implications for human disease derived from a novel murine model

Abstract

Abstract Pancreatic cancer (PC) is a highly lethal malignancy characterized by local tumor aggressiveness and early metastatic dissemination. While surgical resection is used to treat localized cancers, the majority of patients do recur suggesting the presence of disseminated tumor cells (DTC) at the time of surgery. These DTC's represent minimal residual disease. While most patients recur early, a subset recur late due to the reactivation of dormant tumor cells. Currently, the mechanisms of cancer dormancy are poorly understood in part due to a lack of animal models that reflect human disease. Here we describe a murine model of PC dormancy that mimics outcomes in resected human patients. Using single-cell transcriptomics and an assay for chromatin accessibility, we found dormancy is a distinct cellular state from pre or post-dormant cancer cells. Mechanisms of dormancy include increased expression of transcriptional repressor Dec2, which functionally drives quiescence, and monoallelic suppression of mutant KRAS by DNA methylation. Pathway analysis of dormant tumor cell transcriptomics indicated an up-regulation of enzymes involved in linoleic acid metabolism among others. Linoleic acid treatment of tumor cells resulted in inhibited cell proliferation, decreased tumor growth, and an increase in Dec2 expression. We have identified a dormancy gene signature that is distinct from non-dormant PC cells and found that this correlates with human resected patients with long term survivals, and inversely in patients with short term survivals. We demonstrate that dormancy is characterized by large scale transcriptomic changes and global chromatin remodeling. We developed methods for isolating DTCs from the livers of early stage PC patients undergoing resection. Using these methods we have found that the murine dormancy signature correlated with the gene expression of the DTCs and not primary tumor cells indicating this dormancy signature has human relevance with potential novel therapeutic avenues. Citation Format: Anthony S. Casabianca, Crissy Dudgeon, Chris Harris, Subhajyoto De, Mihir Shah, Arthur Roberts, Eric Collisson, Vinod Balachandran, Darren Carpizo. A genetic signature of cancer dormancy: implications for human disease derived from a novel murine model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 121.