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Regulation of pancreatic cancer migration by signal convergence in the epigenome [ChIP-Seq]

ABSTRACT: 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 TNFα and oncogenic MAPK signaling pathways converge to control PDAC cell migration through activation of NF-κB 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 TNFα 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-κB 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE278111 | GEO | 2025/06/26

REPOSITORIES: GEO

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Project description:Immunotherapeutics represent highly promising agents with the potential to improve patient outcomes in a variety of cancer types. Unfortunately, single-agent immunotherapy has achieved limited clinical benefit to date in patients suffering from pancreatic ductal adenocarcinoma (PDAC). This may be due to the presence of a uniquely immunosuppressive tumor microenvironment (TME) present in PDACs, which creates a barrier to effective immune surveillance. Critical obstacles to immunotherapy in PDAC tumors include the dense desmoplastic stroma that acts as a barrier to T-cell infiltration and the high numbers of tumor-associated immunosuppressive cells. We have identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as a significant regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlates with high levels of fibrosis and poor CD8+ cytotoxic T-cell infiltration. Single-agent FAK inhibition (VS-4718) dramatically limited tumor progression, resulting in a doubling of survival in the p48-Cre/LSL-KrasG12D/p53Flox/+ (KPC) mouse model of human PDAC. This alteration in tumor progression was associated with dramatically reduced tumor fibrosis, decreased numbers of tumor-infiltrating immature myeloid cells and immunosuppressive macrophages. We postulated that these desirable effects of FAK inhibition on the TME might render PDAC tumors more sensitive to immunotherapy. Accordingly, we found that VS-4718 rendered the previously unresponsive KPC mouse model responsive to anti-PD1 and anti-CTLA4 antagonists leading to a nearly tripling of survival times. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME thus rendering tumors more responsive to immunotherapy. We treated KP orthotopic tumor-bearing mice with vehicle and FAK inhibitor (FAKi) for 14 days, then extracted total RNA from tumor tissues.

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Regulation of pancreatic cancer migration by signal convergence in the epigenome [ChIP-Seq]

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