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We hypothesize that EMT followed by MET promotes cell population heterogeneity, favouring tumour growth. We developed an EMT model by on and off exposure of epithelial EpH4 cells (E-cells) to TGF\u03b21 that mimics phenotypic EMT (M-cells) and MET. We aimed at understanding whether phenotypic MET is accompanied by molecular and functional reversion back to epithelia by using RNA sequencing, immunofluorescence (IF), proliferation, wound healing, focus formation and mamosphere formation assays as well as cell xenografts in nude mice. Phenotypic reverted epithelial cells (RE-cells) obtained after MET induction presented epithelial morphologies and proliferation rates resembling E cells. However, the RE transcriptomic profile and IF staining of epithelial and mesenchymal markers revealed a uniquely heterogeneous mixture of cell subpopulations with a high self-renewal ability. RE cell heterogeneity was stably maintained for long periods after TGF\u03b21 removal both in vitro and in large tumours derived from the nude mice. Overall, we show that phenotypic reverted epithelial cells (RE cells) do not return to the molecular and functional epithelial state and present mesenchymal features related to aggressiveness and cellular heterogeneity that favour tumour growth in vivo. This work strengthens epithelial cell reprogramming and cellular heterogeneity fostered by inflammatory cues as a tumour growth-promoting factor in vivo.<\/jats:p>","DOI":"10.3390\/biology11071046","type":"journal-article","created":{"date-parts":[[2022,7,12]],"date-time":"2022-07-12T20:52:41Z","timestamp":1657659161000},"page":"1046","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Epithelial-Mesenchymal Plasticity Induced by Discontinuous Exposure to TGF\u03b21 Promotes Tumour Growth"],"prefix":"10.3390","volume":"11","author":[{"given":"Mafalda","family":"Santos","sequence":"first","affiliation":[{"name":"I3S, Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, 4200-135 Porto, Portugal"},{"name":"Ipatimup, Instituto de Patologia e Imunologia Molecular da Universidade do Porto, 4200-465 Porto, 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