c-Rel drives pancreatic cancer metastasis through Fibronectin-Integrin signaling-induced isolation stress resistance and EMT activation

Bakırdögen, D.; Görgülü, K.; Xin, J.; Alcala, S.; Ruiz-Canas, L.; Frank, K.; Wu, N.; Diakopoulos, K. N.; Dai, C.; Öztürk, H.; Demircioglu, D.; Peschke, K.; Ranjan, R.; Fusco, F.; Martinez-Useros, J.; Fernandez-Acenero, M. J.; Chhabra, N. F.; Lopez-Gil, J. C.; Ai, J.; Ruess, D. A.; Kaya-Aksoy, E.; Steiger, K.; Schmidt, F.; Kohlmann, L.; Berninger, A.; Schmid, R. M.; Reichert, M.; Adli, M.; Lesina, M.; Sainz, B.; Algül, H.

doi:10.1101/2025.01.29.635445

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bioRxiv · 10.1101/2025.01.29.635445

c-Rel drives pancreatic cancer metastasis through Fibronectin-Integrin signaling-induced isolation stress resistance and EMT activation

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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.

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Bakırdögen, D., Görgülü, K., Xin, J., Alcala, S., Ruiz-Canas, L., Frank, K., Wu, N., Diakopoulos, K. N., Dai, C., Öztürk, H., Demircioglu, D., Peschke, K., Ranjan, R., Fusco, F., Martinez-Useros, J., Fernandez-Acenero, M. J., Chhabra, N. F., Lopez-Gil, J. C., Ai, J., Ruess, D. A., Kaya-Aksoy, E., Steiger, K., Schmidt, F., Kohlmann, L., Berninger, A., Schmid, R. M., Reichert, M., Adli, M., Lesina, M., Sainz, B., Algül, H.. 2025-02-01. c-Rel drives pancreatic cancer metastasis through Fibronectin-Integrin signaling-induced isolation stress resistance and EMT activation. https://doi.org/10.1101/2025.01.29.635445

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