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Abstract
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.
Highlights
Cellular plasticity confers cancer cells the ability to adapt to microenvironmental changes, a fundamental requirement for tumour progression and metastasis
Previous data report that the epithelial mesenchymal transition (EMT) is promoted by the induction of a transcriptional programme that has been associated with the activation of several key transcriptions factors, including Snail (SNAI1), Slug (SNAI2), Twist and ZEB-1/2
We have recently demonstrated that melanoma cells are able to shift between mesenchymal and amoeboid motility: melanoma cells move mesenchymally in response to pro-inflammatory cytokines, whereas after re-expression of embryonic EphA2 receptor, they achieve an amoeboid motility style giving rise to successful metastatisation [13]
Summary
Cellular plasticity confers cancer cells the ability to adapt to microenvironmental changes, a fundamental requirement for tumour progression and metastasis. Previous data report that the epithelial mesenchymal transition (EMT) is promoted by the induction of a transcriptional programme that has been associated with the activation of several key transcriptions factors, including Snail (SNAI1), Slug (SNAI2), Twist and ZEB-1/2. This transcriptional programme leads to the disruption of adherens junctions, activation of polarized cell motility and increased degradation of ECM through secretion of MMPs [6,7,8]. MAT confers a clear advantage to metastatic processes, very little is known about the molecular events that promote this motility shift [12,13,15]
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