Abstract LB-A28: Super-enhancer signatures of pancreatic ductal adenocarcinoma and associated fibroblasts

Abstract

Abstract Therapeutic targeting of super-enhancers (SEs) has emerged as a promising approach for cancer treatment. To understand how SEs regulate the gene expression of tumors and their microenvironments, we sought to profile the SE landscape in pancreatic ductal adenocarcinoma (PDAC) cell lines and cancer-associated fibroblast (CAF) cells that were derived from different PDAC patients. The global profiling of the H3K27Ac signals in 6 PDAC and 6 CAF cell lines by chromatin immunoprecipitation coupled to sequencing (ChIP-seq) were performed to identify the SE landscapes in each cell line. Our data showed distinct SE landscapes in PDACs and CAFs. A total of 1025 SEs were identified in the PDAC cell lines. Signaling pathways that were significantly enriched among the genes associated with these SEs included targets of c-MYC, PDGFR, EGFR, AP1, uPA and uPAR pathways. Interestingly, wound-healing genes were highly enriched in the PDAC SE analysis; these genes are well known for their roles in cancer stemness and metastasis. 330 SEs were present in more than one PDAC cell line, but only 11 SEs were present in all 6 of the cell lines. Despite this low number of common SEs, the biological pathways of SE-associated genes, including ‘hallmark TNFA signaling via NFkB’ and ‘response to growth factor’, were significantly enriched in all of the PDAC cell lines. The profiling of the CAF cell lines identified a total of 1720 SEs, with 985 SEs present in more than one of the CAF cell lines and 99 SEs were present in all 6 of the CAF cell lines. As expected, the SE-associated genes in CAFs were involved in focal adhesion, extracellular matrix interaction and organization, and platelet activation. Interestingly, the biological pathways of ‘hallmark TNFA signaling via NFkB’ and ‘response to growth factor’ were present in all of the PDAC and CAF cell lines, while the ‘hallmark epithelial mesenchymal transition’ pathway was found only in the 6 CAF cell lines. RNA-Seq analysis of the same cell lines found that the gene expression intensities of the SE-associated genes had a pattern similar to that of the H3K27Ac signals of the SEs, indicating a high correlation between SE activity and gene expression. To functionally validate the identified SEs and the level of enhancement of gene activity by SEs, we are investigating the biological effects of suppressing the SEs associated with critical oncogenes using CRISPR interference. Overall, our study has identified important biological pathways that are controlled by SEs in PDAC cells and CAFs. These observations offer us a means to study the consequences of perturbing the SE network on PDAC and its microenvironment. Citation Format: Shaimaa Hussein, Pawan Noel, Kenian Chen, Lauren Metang, Daniel Von Hoff, Haiyong Han, Yin Lin. Super-enhancer signatures of pancreatic ductal adenocarcinoma and associated fibroblasts [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-A28.