Epithelial-Mesenchymal Plasticity Induced by Discontinuous Exposure to TGFβ1 Promotes Tumour Growth
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 T...
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MDPI AG
2022-07-01
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| Online Access: | https://www.mdpi.com/2079-7737/11/7/1046 |
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| author | Mafalda Santos Marta Ferreira Patrícia Oliveira Nuno Mendes Ana André André F. Vieira Joana B. Nunes Joana Carvalho Sara Rocha Mafalda Azevedo Daniel Ferreira Inês Reis João Vinagre Joana Paredes Alireza Heravi-Moussavi Jorge Lima Valdemar Máximo Angela Burleigh Calvin Roskelley Fátima Carneiro David Huntsman Carla Oliveira |
| author_facet | Mafalda Santos Marta Ferreira Patrícia Oliveira Nuno Mendes Ana André André F. Vieira Joana B. Nunes Joana Carvalho Sara Rocha Mafalda Azevedo Daniel Ferreira Inês Reis João Vinagre Joana Paredes Alireza Heravi-Moussavi Jorge Lima Valdemar Máximo Angela Burleigh Calvin Roskelley Fátima Carneiro David Huntsman Carla Oliveira |
| author_sort | Mafalda Santos |
| collection | DOAJ |
| description | 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 TGFβ1 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 TGFβ1 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. |
| first_indexed | 2024-03-09T03:41:29Z |
| format | Article |
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| issn | 2079-7737 |
| language | English |
| last_indexed | 2024-03-09T03:41:29Z |
| publishDate | 2022-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biology |
| spelling | doaj.art-7302372388394956b9b27c7225a965ca2023-12-03T14:40:42ZengMDPI AGBiology2079-77372022-07-01117104610.3390/biology11071046Epithelial-Mesenchymal Plasticity Induced by Discontinuous Exposure to TGFβ1 Promotes Tumour GrowthMafalda Santos0Marta Ferreira1Patrícia Oliveira2Nuno Mendes3Ana André4André F. Vieira5Joana B. Nunes6Joana Carvalho7Sara Rocha8Mafalda Azevedo9Daniel Ferreira10Inês Reis11João Vinagre12Joana Paredes13Alireza Heravi-Moussavi14Jorge Lima15Valdemar Máximo16Angela Burleigh17Calvin Roskelley18Fátima Carneiro19David Huntsman20Carla Oliveira21I3S, Instituto de Investigação e Inovação em Saúde, 4200-135 Porto, PortugalI3S, Instituto de Investigação e Inovação em Saúde, 4200-135 Porto, PortugalI3S, Instituto de Investigação e Inovação em Saúde, 4200-135 Porto, PortugalI3S, Instituto de Investigação e Inovação em Saúde, 4200-135 Porto, PortugalI3S, Instituto de Investigação e Inovação em Saúde, 4200-135 Porto, PortugalI3S, Instituto de Investigação e Inovação em Saúde, 4200-135 Porto, PortugalI3S, Instituto de Investigação e Inovação em Saúde, 4200-135 Porto, PortugalI3S, Instituto de Investigação e Inovação em Saúde, 4200-135 Porto, PortugalI3S, Instituto de Investigação e Inovação em Saúde, 4200-135 Porto, PortugalIpatimup, Instituto de Patologia e Imunologia Molecular da Universidade do Porto, 4200-465 Porto, PortugalI3S, Instituto de Investigação e Inovação em Saúde, 4200-135 Porto, PortugalIpatimup, Instituto de Patologia e Imunologia Molecular da Universidade do Porto, 4200-465 Porto, PortugalI3S, Instituto de Investigação e Inovação em Saúde, 4200-135 Porto, PortugalI3S, Instituto de Investigação e Inovação em Saúde, 4200-135 Porto, PortugalBritish Columbia Cancer Agency, Vancouver, BC V5Z4E6, CanadaI3S, Instituto de Investigação e Inovação em Saúde, 4200-135 Porto, PortugalI3S, Instituto de Investigação e Inovação em Saúde, 4200-135 Porto, PortugalBritish Columbia Cancer Agency, Vancouver, BC V5Z4E6, CanadaBritish Columbia Cancer Agency, Vancouver, BC V5Z4E6, CanadaI3S, Instituto de Investigação e Inovação em Saúde, 4200-135 Porto, PortugalBritish Columbia Cancer Agency, Vancouver, BC V5Z4E6, CanadaI3S, Instituto de Investigação e Inovação em Saúde, 4200-135 Porto, PortugalTransitions 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 TGFβ1 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 TGFβ1 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.https://www.mdpi.com/2079-7737/11/7/1046METcellular heterogeneityself-RenewalEMTtumourigenic potential |
| spellingShingle | Mafalda Santos Marta Ferreira Patrícia Oliveira Nuno Mendes Ana André André F. Vieira Joana B. Nunes Joana Carvalho Sara Rocha Mafalda Azevedo Daniel Ferreira Inês Reis João Vinagre Joana Paredes Alireza Heravi-Moussavi Jorge Lima Valdemar Máximo Angela Burleigh Calvin Roskelley Fátima Carneiro David Huntsman Carla Oliveira Epithelial-Mesenchymal Plasticity Induced by Discontinuous Exposure to TGFβ1 Promotes Tumour Growth Biology MET cellular heterogeneity self-Renewal EMT tumourigenic potential |
| title | Epithelial-Mesenchymal Plasticity Induced by Discontinuous Exposure to TGFβ1 Promotes Tumour Growth |
| title_full | Epithelial-Mesenchymal Plasticity Induced by Discontinuous Exposure to TGFβ1 Promotes Tumour Growth |
| title_fullStr | Epithelial-Mesenchymal Plasticity Induced by Discontinuous Exposure to TGFβ1 Promotes Tumour Growth |
| title_full_unstemmed | Epithelial-Mesenchymal Plasticity Induced by Discontinuous Exposure to TGFβ1 Promotes Tumour Growth |
| title_short | Epithelial-Mesenchymal Plasticity Induced by Discontinuous Exposure to TGFβ1 Promotes Tumour Growth |
| title_sort | epithelial mesenchymal plasticity induced by discontinuous exposure to tgfβ1 promotes tumour growth |
| topic | MET cellular heterogeneity self-Renewal EMT tumourigenic potential |
| url | https://www.mdpi.com/2079-7737/11/7/1046 |
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