Mesenchymal to amoeboid transition is associated with stem-like features of melanoma cells

Cell Communication and Signaling

Research

Paolo Gandellini¹  Maurizio Callari¹  Luigi Ippolito²  Matteo Ramazzotti²  Maria Letizia Taddei²  Andrea Morandi²  Elisa Giannoni²  Paola Chiarugi³ 

[1] Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy;Department of Experimental and Clinical Biomedical Sciences, Tuscany Tumor Institute, University of Florence, viale Morgagni 50, 50134, Florence, Italy;Department of Experimental and Clinical Biomedical Sciences, Tuscany Tumor Institute, University of Florence, viale Morgagni 50, 50134, Florence, Italy;Center for Research, Transfer and High Education ‘Study at Molecular and Clinical Level of Chronic, Inflammatory, Degenerative and Neoplastic Disorders for the Development on Novel Therapies’, Florence, Italy;

关键词: Melanoma;    Cell plasticity;    Amoeboid motility;    Stemness;    EphA2;   

DOI  :  10.1186/1478-811X-12-24

 received in 2013-11-08, accepted in 2014-03-11,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundCellular plasticity confers cancer cells the ability to adapt to microenvironmental changes, a fundamental requirement for tumour progression and metastasis. The epithelial to mesenchymal transition (EMT) is a transcriptional programme associated with increased cell motility and stemness. Besides EMT, the mesenchymal to amoeboid transition (MAT) has been described during tumour progression but to date, little is known about its transcriptional control and involvement in stemness. The aim of this manuscript is to investigate (i) the transcriptional profile associated with the MAT programme and (ii) to study whether MAT acquisition in melanoma cancer cells correlates with clonogenic potential to promote tumour growth.ResultsBy using a multidisciplinary approach, we identified four different treatments able to induce MAT in melanoma cells: EphA2 overexpression, Rac1 functional inhibition using its RacN17 dominant negative mutant, stimulation with Ilomastat or treatment with the RhoA activator Calpeptin. First, gene expression profiling identified the transcriptional pathways associated with MAT, independently of the stimulus that induces the MAT programme. Notably, gene sets associated with the repression of mesenchymal traits, decrease in the secretion of extracellular matrix components as well as increase of cellular stemness positively correlate with MAT. Second, the link between MAT and stemness has been investigated in vitro by analysing stemness markers and clonogenic potential of melanoma cells undergoing MAT. Finally, the link between MAT inducing treatments and tumour initiating capability has been validated in vivo.ConclusionTaken together, our results demonstrate that MAT programme in melanoma is characterised by increased stemness and clonogenic features of cancer cells, thus sustaining tumour progression. Furthermore, these data suggest that stemness is not an exclusive feature of cells undergoing EMT, but more generally is associated with an increase in cellular plasticity of cancer cells.

【 授权许可】

Unknown   
© Taddei et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.