Integrin-TGFβ axis induces partial EMT in basal-like cells to lead collective invasion

El-Gammal, A.; Jansen, L.; Verhagen, M. P.; Kremer, H.; Soufi, S.; Masoudnia, M.; Westland, D.; Bult, P.; Fodde, R.; Verstegen, M. M. A.; Gloerich, M.; van Mil, S. W. C.; Khalil, A. A.

doi:10.1101/2025.04.04.647177

bioRxiv · 10.1101/2025.04.04.647177

Integrin-TGFβ axis induces partial EMT in basal-like cells to lead collective invasion

El-Gammal, A.·Jansen, L.·Verhagen, M. P.·Kremer, H.·Soufi, S.·Masoudnia, M.·Westland, D.·Bult, P.·Fodde, R.·Verstegen, M. M. A.·Gloerich, M.·van Mil, S. W. C.·Khalil, A. A.

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Abstract

Collective invasion is the predominant mode of cancer cell dissemination in breast cancer and represents the initial step of metastatic spread. Basal-like leader cells drive this process by maintaining cell-cell junctions with the follower cells while extending actin-rich protrusions and remodeling the collagen I-rich peritumoral stroma. These features resemble those of individually-invading cells following epithelial-to-mesenchymal transition (EMT). However, how leader cells acquire these traits while preserving cohesion within the collective remains unclear. Here, we identify a collagen I-responsive subset of basal-like cells that coexpress cytoskeletal, extracellular matrix (ECM)-remodeling, and epithelial junction genes. We show that integrin 2 (Itg2) links collagen I engagement to mesenchymal reprogramming by inducing inhibin beta A (INHBA) expression and activating tumor growth factor {beta} (TGF{beta}) signaling. This, in turn, upregulates vimentin while preserving epithelial junction gene expression. In parallel, Itg2 promotes ECM degradation through a TGF{beta}-independent mechanism. This study identifies Itg2-TGF{beta} axis as a key regulator of partial EMT and leader cell function, highlighting it as a potential therapeutic target in aggressive breast cancers.

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El-Gammal, A., Jansen, L., Verhagen, M. P., Kremer, H., Soufi, S., Masoudnia, M., Westland, D., Bult, P., Fodde, R., Verstegen, M. M. A., Gloerich, M., van Mil, S. W. C., Khalil, A. A.. 2025-04-05. Integrin-TGFβ axis induces partial EMT in basal-like cells to lead collective invasion. https://doi.org/10.1101/2025.04.04.647177

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