Regulation of pancreatic cancer migration by signal convergence in the epigenome

Pancreatic ductal adenocarcinoma (PDAC) is frequently diagnosed at an advanced, metastatic stage. PDAC treatment is challenging due to high tumor cell plasticity, tumor heterogeneity, and a dense tumor microenvironment (TME), all of which strongly influence tumor metastasis. While mutations in the KRAS gene characterize PDAC, inflammatory signaling from the TME accelerates tumor progression, metastasis, and therapy resistance. While individual roles of oncogenic and inflammatory signaling in promoting PDAC progression have been studied extensively, the epigenetic and transcriptional mechanisms by which they function combinatorially in metastasis remain unclear. Our study elucidates how inflammatory TNFalpha and oncogenic MAPK signaling pathways converge to control PDAC cell migration through activation of NF-kappaB and AP1 transcription factors, respectively. Combining single-cell RNA sequencing (scRNAseq) analyses, multiplex immunofluorescence staining, in vitro, and in vivo studies, we unveil that the simultaneous activation of these pathways with TNF-alpha and EGF induces the expression of specific genes associated with cell motility and migration. We show that combinatorial induced genes are co-bound by FOSL1 and RELA. Remarkably, inhibition of NF-kappaB transcriptional activity using glucocorticoid receptor (GR) mixed agonists significantly reduces RNA polymerase II across the target genes and inhibits cell migration. These findings highlight the potential of GR agonists, commonly utilized to alleviate chemotherapy side effects, in mitigating PDAC tumor migration. Our study offers promising avenues for developing mechanism-based therapeutic strategies in PDAC management.