Epithelial-Mesenchymal Plasticity Induced by Discontinuous Exposure to TGFß1 Promotes Tumour Growth

Data de publicação:

Autores da FMUP

  • Joana Cancela De Amorim Falcão Paredes

    Autor

  • Valdemar De Jesus Conde Máximo

    Autor

  • Maria De Fátima Machado Henriques Carneiro

    Autor

  • Carla Isabel Gonçalves De Oliveira

    Autor

Participantes de fora da FMUP

  • Santos, M
  • Ferreira, M
  • Oliveira, P
  • Mendes, N
  • Andre, A
  • Vieira, AF
  • Nunes, JB
  • Carvalho, J
  • Rocha, S
  • Azevedo, M
  • Ferreira, D
  • Reis, I
  • Vinagre, J
  • Heravi Moussavi, A
  • Lima, J.
  • Burleigh, A
  • Roskelley, C
  • Huntsman, D

Unidades de investigação

Abstract

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.

Dados da publicação

ISSN/ISSNe:
2079-7737, 2079-7737

BIOLOGY-BASEL  Multidisciplinary Digital Publishing Institute (MDPI)

Tipo:
Article
Páginas:
1046-
Link para outro recurso:
www.scopus.com

Citações Recebidas na Web of Science: 3

Citações Recebidas na Scopus: 3

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Keywords

  • MET; cellular heterogeneity; self-Renewal; EMT; tumourigenic potential

Financiamento

Proyectos asociados

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Studying the value of embryonic stem cell (ESC) markers in breast cancer pathology

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