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A gene regulatory network to control EMT programs in development and disease
(Springer Science and Business Media LLC, 2019) Galceran, J. (Juan); Kass-Youssef, K. (Khalil); García-Asencio, F. (Francisco); Ocaña, O.H. (Oscar H.); Rago, L. (Luciano); Arcas, A. (Aída); Fazilaty, H. (Hassan); Nieto, M.A. (M. Ángela)
The Epithelial to Mesenchymal Transition (EMT) regulates cell plasticity during embryonic development and in disease. It is dynamically orchestrated by transcription factors (EMT-TFs), including Snail, Zeb, Twist and Prrx, all activated by TGF-β among other signals. Here we find that Snail1 and Prrx1, which respectively associate with gain or loss of stem-like properties and with bad or good prognosis in cancer patients, are expressed in complementary patterns during vertebrate development and in cancer. We show that this complementarity is established through a feedback loop in which Snail1 directly represses Prrx1, and Prrx1, through direct activation of the miR-15 family, attenuates the expression of Snail1. We also describe how this gene regulatory network can establish a hierarchical temporal expression of Snail1 and Prrx1 during EMT and validate its existence in vitro and in vivo, providing a mechanism to switch and select different EMT programs with important implications in development and disease.