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C-Rel drives pancreatic cancer metastasis through Fibronectin-Integrin signaling-induced isolation stress resistance and EMT activation [Cut&Run]

ABSTRACT: Pancreatic ductal adenocarcinoma remains one of the deadliest malignancies, with limited treatment options and a high recurrence rate. Recurrence happens often with metastasis, for which cancer cells must adapt to isolation stress to successfully colonize distant organs. While the fibronectin-integrin axis has been implicated in this adaptation, its regulatory mechanisms require further elaboration. Here, we identify c-Rel as an oncogenic driver in PDAC, promoting epithelial-to-mesenchymal transition (EMT) plasticity, extracellular matrix (ECM) remodeling, and resistance to isolation stress. Mechanistically, c-Rel directly regulates fibronectin (Fn1) and CD61 (itgb3) transcription, enhancing cellular plasticity and survival under anchorage-independent conditions. Fibronectin is not essential for EMT, but its absence significantly impairs metastatic colonization, highlighting a tumor-autonomous role for FN1 in isolation stress adaptation. These findings establish c-Rel as a key regulator of PDAC metastasis by controlling circulating tumor cell (CTC) niche and survival, suggesting that targeting the c-Rel–fibronectin–integrin axis could provide new therapeutic strategies to mitigate disease progression and recurrence.

ORGANISM(S): Mus musculus

PROVIDER: GSE291889 | GEO | 2026/03/11

REPOSITORIES: GEO

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous cancer in which differences in survival rates might be related to a variety in gene expression profiles. Although the molecular biology of PDAC begins to be revealed, genes or pathways that specifically drive tumour progression or metastasis are not well understood. Therefore, we performed microarray analyses on whole-tumour samples of 2 human PDAC subpopulations with similar clinicopathological features, but extremely distinct survival rates after potentially curative surgery, i.e., good outcome (OS and DFSM-bM-^@M-^I>M-bM-^@M-^I50M-bM-^@M-^Imonths) versus bad outcome (OSM-bM-^@M-^I<M-bM-^@M-^I19M-bM-^@M-^Imonths and DFSM-bM-^@M-^I<M-bM-^@M-^I7M-bM-^@M-^Imonths). Additionally, liver- and peritoneal metastases were analysed and compared to primary cancer tissue. The integrin and ephrin receptor families were upregulated in all PDAC samples, irrespective of outcome, supporting an important role of the interaction between pancreatic cancer cells and the surrounding desmoplastic reaction in tumorigenesis and cancer progression. Moreover, some components, such as ITGB1 and EPHA2, were upregulated in PDAC samples with a poor outcome, Additionally, overexpression of the non-canonical Wnt/M-NM-2-catenin pathway and EMT genes in PDAC samples with bad versus good outcome suggests their contribution to the invasiveness of pancreatic cancer, with M-NM-2-catenin being also highly upregulated in metastatic tissue. Thus, we conclude that components of the integrin and ephrin pathways and EMT-related genes might serve as molecular markers in pancreatic cancer as their expression seems to be related with prognosis. Microarray analysis was performed on 'Good' and 'Bad' patient samples (samples with similar pathological characteristics were chosen based on the definition of the 2 diverse survival outcome groups and the required RIN values above 7.1), on surrounding non-tumoural pancreatic control samples, liver metastasis (LM) and peritoneal metastasis (PM). Comparisons between good vs. control, bad vs. control, good vs. bad, and primary pancreatic cancer versus metastasis were performed.

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C-Rel drives pancreatic cancer metastasis through Fibronectin-Integrin signaling-induced isolation stress resistance and EMT activation [Cut&Run]

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