Abstract
Despite the general focus on an invasive and de-differentiated phenotype as main driver of cancer metastasis, in melanoma patients many metastatic lesions display a high degree of pigmentation, indicative for a differentiated phenotype. Indeed, studies in mice and fish show that melanoma cells switch to a differentiated phenotype at secondary sites, possibly because in melanoma differentiation is closely linked to proliferation through the lineage-specific transcriptional master regulator MITF. Importantly, while a lot of effort has gone into identifying factors that induce the de-differentiated/invasive phenotype, it is not well understood how the switch to the differentiated/proliferative phenotype is controlled. We identify collagen as a contributor to this switch. We demonstrate that collagen stiffness induces melanoma differentiation through a YAP/PAX3/MITF axis and show that in melanoma patients increased collagen abundance correlates with nuclear YAP localization. However, the interrogation of large patient datasets revealed that in the context of the tumour microenvironment, YAP function is more complex. In the absence of fibroblasts, YAP/PAX3-mediated transcription prevails, but in the presence of fibroblasts tumour growth factor-β suppresses YAP/PAX3-mediated MITF expression and induces YAP/TEAD/SMAD-driven transcription and a de-differentiated phenotype. Intriguingly, while high collagen expression is correlated with poorer patient survival, the worst prognosis is seen in patients with high collagen expression, who also express MITF target genes such as the differentiation markers TRPM1, TYR and TYRP1, as well as CDK4. In summary, we reveal a distinct lineage-specific route of YAP signalling that contributes to the regulation of melanoma pigmentation and uncovers a set of potential biomarkers predictive for poor survival.
Highlights
Phenotypes impact on melanoma progression, and many in vitro studies and mouse models have concluded that it is the ‘de-differentiated/invasive’ phenotype that is more ‘aggressive’ and ‘metastatic’
In line with YAP regulating MITF expression, we found that YAP depletion resulted in the reduced expression of MITF target genes, including differentiation and proliferation markers (Fig. 4d), and melanoma cell proliferation was significantly reduced after YAP knockdown (Fig. 4e and Supplementary Figure S5)
We considered that the source of the collagen within a tumour could vary; we have previously shown that collagen deposition in vivo can be performed by melanoma cells themselves [28], but it is well known that resident fibroblasts can contribute to matrix deposition [29]
Summary
Phenotypes impact on melanoma progression, and many in vitro studies and mouse models have concluded that it is the ‘de-differentiated/invasive’ phenotype that is more ‘aggressive’ and ‘metastatic’. In patients many metastatic lesions display a high degree of pigmentation and as such differentiation. While the pigmented melanoma cells switched off this trait during early invasion and dissemination, the less differentiated phenotype was not maintained at secondary sites, and metastases were highly pigmented [3]. This suggests that differentiation was induced in these secondary tumours most probably by factors from the microenvironment
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