Lines of investigation
Our main interest is the study of cell behaviour in development and disease, in particular associated with cell movements. We have been working on the process of epithelial to mesenchymal transition (EMT) fundamental for the development of tissues and organs which cells undergo massive cell migrations. We have also found that pathological activation of the EMT in the adult leads to several prominent pathologies. As such, aberrant activation of EMT in tumours leads to the acquisition of invasive and migratory properties. We have extended the study of some EMT inducing factors, such as Snail, to different pathologies. As such, an aberrant activation of Snail leads to the development of achondroplasia (the most common form of dwarfism in humans) and osteomalacia (bone demineralization in the adult). Going back to fundamental processes at early development, we have shown that the interplay between Snail factors and another transcription factor (Sox3) determines embryonic territories at gastrulation, ensuring the formation of the nervous system and more recently, we have found the mechanism that drives heart positioning.
Metastasis is the cause of the vast majority of cancer-associated deaths, but the underlying mechanisms remain poorly understood. The invasion and dissemination steps during carcinoma progression have been associated with EMT. However, we have shown that while EMT is important for the acquisition of motility and invasive properties in cancer cells, its abrogation is required for these migratory cancer cells to colonize distant organs and progress to the metastatic state. This also has an impact on the design of therapeutic strategies in cancer, as inhibiting EMT (and therefore, motility) when cells have already disseminated from the primary tumour will indeed favour metastasis formation.
The EMT has been also associated with the development of organ fibrosis, accompanied by massive accumulation of extracellular matrix, mainly collagen fibres secreted by an excess of myofibroblasts. Fibrosis appears in different organs such as the kidney, the liver, the lung or the heart and it concurs with a progressive reduction in organ function and eventual organ failure. Thus, it is crucial to understand the mechanisms by which fibrosis develops, and one key question is the origin of myofibroblasts, that has been debated until recently. Some data indicated that they were the result of an EMT undergone by the epithelial cells, while lineage analysis suggested that this was not the case. We have shown that the activation of EMT is required for development of renal fibrosis but, importantly, that renal epithelial cells are not the source of myofibroblasts. As such, fibrosis develops after renal epithelial cells undergo a partial EMT by which they dedifferentiate but remain integrated in the tubules. These damaged epithelial cells send signals to the interstitium that in turn favor (i) the differentiation of myofibroblasts from interstitial fibroblasts, and (ii) the recruitment of bone marrow-derived mesenchymal cells and macrophages, therefore favoring fibrogenesis and sustaining inflammation, the hallmarks of fibrosis. Furthermore, we have shown that fibrosis can be attenuated by the systemic injection of EMT inhibitors, opening new avenues for the treatment of fibrotic diseases.
In our studies we use mouse, chick and zebrafish as experimental models for loss or gain and function analyses together with cultured cells and samples from patients. We are currently interested in i) investigating new regulatory networks that control cell movements and plasticity, iii) tracking the movements of embryonic cells that regulate organ positioning, iv) tracking the movement and plasticity of cancer cells from the primary tumor to metastatic foci, and v) studying the complexity of cell plasticity to better understand organ formation and degeneration, aiming at proposing better therapeutic strategies. We use zebrafish, chicken and mouse as
- A gene regulatory network to control EMT programs in development and disease Fazilaty H, Rago L, Kass Youssef K, Ocaña OH, Garcia-Asencio F, Arcas A, Galceran J, Nieto MA Nature Communications 2019 10:5115 https://doi.org/10.1038/s41467-019-13091-8
- MicroRNAs Establish the Right-Handed Dominance of the Heart Laterality Pathway in Vertebrates Rago L, Castroviejo N, Fazilaty H, Garcia-Asencio F, Ocaña OH, Galcerán J, Nieto MA Developmental Cell 2019 51(4):UNSP e3432 https://doi.org/10.1016/j.devcel.2019.09.012
- A right-handed signalling pathway drives heart looping in vertebrates Ocaña OH, Coskun H, Minguillon C, Murawala P, Tanaka EM, Galceran J, Muñoz-Chapuli R, Nieto MA Nature 2017 549(7670):86 https://doi.org/10.1038/nature23454
- EMT: 2016 Nieto MA, Huang RY, Jackson RA, Thiery JP Cell 2016 166(1):21 https://doi.org/10.1016/j.cell.2016.06.028
- Snail1-induced partial epitelial-to-mesenchymal transition drives renal fibrosis in mice and can be targeted to reverse established disease Grande MT, Sanchez-Laorden B, Lopez-Blau C, de Frutos CA, Boutet A, Arevalo M, Grant Rowe R, Weiss SJ, Lopez-Novoa JM, Nieto MA Nat Med 2015 21(9):989 https://doi.org/10.1038/nm.3901