Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies, with limited treatment options and a high recurrence rate. Recurrence often occurs 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.

We utilized genetically engineered PDAC mouse models with c-Rel knockout, overexpression and fibronectin (FN1) depletion, alongside in vitro assays, to assess EMP, extracellular matrix (ECM) remodeling, and resistance to anchorage-independent growth. Functional analyses, including transcriptomics, Cut&Run, flow cytometry, immunohistochemistry, and metastatic assays, were performed to elucidate the role of c-Rel in fibronectin–integrin signaling during PDAC progression.

We identified c-Rel as an oncogenic driver in PDAC that promotes EMP, ECM remodeling, and survival under isolation stress. c-Rel directly regulates FN1 and CD61/integrin β3 (ITGB3) transcription, enhancing cellular adaptability in metastatic settings. While FN1 is dispensable for EMT, its absence significantly impairs metastatic colonization and anchorage-independent growth.

Our findings suggest that c-Rel can regulate PDAC progression and metastasis by modulating the tumor microenvironment and stress resistance. Targeting the c-Rel–fibronectin–integrin axis may offer novel therapeutic strategies to mitigate disease progression.