PO-096 Defining the role of Myc in the pancreatic cancer super enhancer network

Abstract

IntroductionCell behaviour and identity are in great part determined by transcriptional switches present in the genome that are referred to as super-enhancers (SEs). The transcription factor Myc coordinates several physiological processes required for cell growth, proliferation and spread and its expression is deregulated in the majority of cancers. Our recent studies have shown that Myc deregulation in a KRasG12D-driven mouse model drives immediate progression to aggressive and inflammatory pancreatic ductal adenocarcinoma (PDAC) accompanied by a profound desmoplastic response. Subsequent Myc de-activation triggers immediate regression of the tumour microenvironment and death of tumour cells. The complex phenotypic changes that accompany the Myc-driven transition to PDAC suggest that Myc plays a key role in driving the pancreatic cancer SE network. However, it remains unclear whether Myc establishes the PDAC SE or, instead, acts as the switch that activates a pre-configured SE network. To distinguish between these possibilities, we have addressed whether the phenotypic and gene expression changes that Myc engages in pancreatic epithelium are accompanied by modifications in the underlying tumour cell epigenome.Material and methodsPrimary tumour cell lines were isolated from our mouse model p48-cre;LSL-KrasG12D/+;Rosa-LSL-MycERTAM, where Myc can be switch on and off at will solely in the pancreatic epithelium. ATAC-seq and ChIP-seq was used to identify Myc-dependent changes in the accessible chromatin and signature epigenetic markers, respectively.Results and discussionsWe observe widespread Myc-dependent changes in gene expression and pro-tumorigenic signalling molecules, including PD-L1 (Programmed death-ligand 1), indicating rapid engagement of the SE network by Myc. Despite these changes in gene expression, we observe no significant accompanying qualitative changes in chromatin accessibility or the H3K27ac landscape. For instance, Myc binds the PD-L1 promoter and regulates its expression in a cell autonomous manner in the pancreatic tumour cell line in the absence of any changes in chromatin accessibility at the PD-L1 locus.ConclusionOur data indicate that Myc does not configure the SE landscape but, instead, serves as a master switch to engage it. Therefore, abrogating Myc’s engagement of the SE network may provide a novel therapeutic strategy for the treatment of pancreatic cancer.