Epithelial-Mesenchymal Plasticity Induced by Discontinuous Exposure to TGF beta 1 Promotes Tumour Growth

• Tipo: Artigo em Revista Científica Internacional
• Data: 2022

Autores

Santos, M (Autor) Outra; Ferreira, M (Autor) Outra; Oliveira, P (Autor) Outra; Mendes, N (Autor) Outra; Andre, A (Autor) Outra; Vieira, AF (Autor) Outra; Nunes, JB (Autor) Outra; Carvalho, J (Autor) Outra; Rocha, S (Autor) Outra; Azevedo, M (Autor) Outra; Ferreira, D (Autor) Outra; Reis, I (Autor) Outra; Vinagre, J (Autor) Outra; Paredes, J (Autor) Outra; Heravi Moussavi, A (Autor) Outra; Lima, J (Autor) FMUP; Maximo, V (Autor) FMUP; Burleigh, A (Autor) Outra; Roskelley, C (Autor) Outra; Carneiro F (Autor) FMUP; Huntsman, D (Autor) Outra; Oliveira, C (Autor) Outra

Revista

Título: BIOLOGY-BASEL

Vol. 11

Página Final: 1046

Editora: MDPI

Indexação

ISI Web of Knowledge - 0 Citações

Scopus

Outras Informações

ID Authenticus: P-00V-YEN

DOI: 10.3390/biology11071046

Abstract (EN): Simple Summary In this manuscript, we used a non-genetically manipulated EMT/MET cell line model to demonstrate that epithelial mesenchymal plasticity occurring in normal cells generates co-existing phenotypically and functionally divergent cell subpopulations which result in fast growing tumours in vivo. Transitions between epithelial and mesenchymal cellular states (EMT/MET) contribute to cancer progression. 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 beta 1 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 beta 1 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.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 17