Abstract 1481: MAPK and NF-kappaB signaling converge on the epigenome to transcriptionally activate genes involved in pancreatic cancer metastasis
Authors: Aggrey-Fynn Joana E. , Hamdan Feda H. , Wixom Alexander Q. , Ekstrom Thomas L. , Johnsen Steven A. 
Published: June 2023

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent and highly aggressive type of pancreatic neoplasm. Unfortunately, most patients will present with unresectable, locally advanced, or metastatic disease at the time of diagnosis. Current treatment methods (gemcitabine and nab-paclitaxel, FOLFIRINOX) are not sufficient for patients with late-stage disease and only modestly improve survival. Difficulties in treating PDAC lie in the characteristics of PDAC tumors. They are highly heterogeneous, have multiple signaling pathway alterations, and are highly metastatic with a dense tumor microenvironment (TME). Hence, PDAC remains one of the most lethal malignancies with a 5-year survival rate below 10%.The KRAS mutation is a hallmark of PDAC, occurring early in 95% of pancreatic neoplasms. The mutant KRAS protein constitutively activates the mitogen-activated protein kinase (MAPK) signaling pathway to sustain PDAC pathogenesis. Although the mutant KRAS gene is the initiating molecular alteration, chronic inflammation accelerates PDAC progression to a highly aggressive and therapy-resistant cancer. Our study shows that MAPK and the nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) inflammatory signaling pathway synergize to promote PDAC progression. Live cell imaging analysis of PDAC cell lines after the simultaneous hyperactivation of MAPK and NF-κB signaling by epidermal growth factor (EGF) and tumor necrosis factor alpha respectively (TNF alpha), showed significant increases in cell migration. An integrated genome-wide epigenetic and transcriptomic analysis (ChIPseq and RNAseq) after the simultaneous stimulation of both pathways revealed significant increases in the occupancy of the active mark, H3K27ac. This was observed around transcription start sites of a subset of genes involved in cell polarity, migration, and subtype switch, processes known to be important for tumor aggressiveness. Epigenome mapping of the transcription factors FOSL1 and RELA, which are downstream targets of the MAPK and NF-κB signaling pathways respectively, show their co-occupancy in the H3K27ac-enriched regions. Furthermore, loss-of-function approaches show the synergistic effect of both MAPK and NF-κB hyperactivation on the migration capacity in vitro and in vivo. Based on these observations, we aim to delineate the molecular mechanism involved in the synergism, investigate the role of the TME, and decipher the signaling interactions between PDAC tumor cells and cells of the TME. This study is the first comprehensive analysis of the synergism between MAPK and NF-κB signaling and will provide novel insights into the development of mechanism-based therapeutic approaches.
Citation Format: Joana E. Aggrey-Fynn, Feda H. Hamdan, Alexander Q. Wixom, Thomas L. Ekstrom, Steven A. Johnsen. MAPK and NF-kappaB signaling converge on the epigenome to transcriptionally activate genes involved in pancreatic cancer metastasis [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 1481.