RAS-induced transformation of mammary epithelial cells relies on ZEB1-dependent cellular reprogramming via a paracrine process

De Blander, H.; Tonon, L.; Fauvet, F.; Pommier, R. M.; Lamblot, C.; Benhassoun, R.; Angileri, F.; Gibert, B.; Ouzounova, M.; Morel, A.-P.; Puisieux, A.

doi:10.1101/2022.06.23.497180

bioRxiv · 10.1101/2022.06.23.497180

RAS-induced transformation of mammary epithelial cells relies on ZEB1-dependent cellular reprogramming via a paracrine process

De Blander, H.·Tonon, L.·Fauvet, F.·Pommier, R. M.·Lamblot, C.·Benhassoun, R.·Angileri, F.·Gibert, B.·Ouzounova, M.·Morel, A.-P.·Puisieux, A.

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Abstract

While uncommon in breast cancers, oncogenic activation of the RAS/MAPK signalling pathway is frequent in claudin-low (CL) tumours, a subtype of breast malignancies enriched in features of epithelial-mesenchymal transition (EMT), suggesting an interplay between RAS activation and EMT. Using inducible models of human mammary epithelial cells, we show that RAS-mediated transformation relies on cellular reprogramming governed by the EMT-inducing transcription factor ZEB1. The path to ZEB1 induction involves a paracrine process: cells entering a senescent state following RAS activation release proinflammatory cytokines, notably IL-6 and IL-1 which promote ZEB1 expression and activity in neighbouring cells, thereby fostering their malignant transformation. Collectively, our findings unveil a previously unprecedented role for senescence in bridging RAS activation and EMT over the course of malignant transformation of human mammary epithelial cells.

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De Blander, H., Tonon, L., Fauvet, F., Pommier, R. M., Lamblot, C., Benhassoun, R., Angileri, F., Gibert, B., Ouzounova, M., Morel, A.-P., Puisieux, A.. 2022-06-26. RAS-induced transformation of mammary epithelial cells relies on ZEB1-dependent cellular reprogramming via a paracrine process. https://doi.org/10.1101/2022.06.23.497180

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