Abstract
Melanoma is a highly aggressive tumour that can metastasize very early in disease progression. Notably, melanoma can disseminate using amoeboid invasive strategies. We show here that high Myosin II activity, high levels of ki-67 and high tumour-initiating abilities are characteristic of invasive amoeboid melanoma cells. Mechanistically, we find that WNT11-FZD7-DAAM1 activates Rho-ROCK1/2-Myosin II and plays a crucial role in regulating tumour-initiating potential, local invasion and distant metastasis formation. Importantly, amoeboid melanoma cells express both proliferative and invasive gene signatures. As such, invasive fronts of human and mouse melanomas are enriched in amoeboid cells that are also ki-67 positive. This pattern is further enhanced in metastatic lesions. We propose eradication of amoeboid melanoma cells after surgical removal as a therapeutic strategy.
Highlights
Melanoma is a highly aggressive tumour that can metastasize very early in disease progression
We show that the invasive fronts of human primary melanomas are enriched in amoeboid invading and proliferating cells expressing non-canonical Wnt and cancer stem cell markers
The transcriptomes of amoeboid A375M2 melanoma cells were compared to A375M2 cells treated with ROCK1/2 inhibitors (ROCKi) or blebbistatin, a direct Myosin II inhibitor, or compared to intrinsically less amoeboid and less metastatic A375P melanoma cells with lower Myosin II activity10,12,15. single-sample gene set enrichment analysis (ssGSEA) analysis revealed that A375M2 cells were enriched in different gene signatures that confer essential attributes of stem cell-like properties, including neural crest (NC) genes, cancer stem cell or embryonic stem cell signatures (Fig. 1a)
Summary
Melanoma is a highly aggressive tumour that can metastasize very early in disease progression. The highly metastatic and therapy-resistant features of melanoma have been linked to its NC-like phenotype with stemness properties[1,2,3,4]. In epithelial tumours, acquisition of a migratory and invasive phenotype via EMT has been linked to the increase in stem cell-like properties[17]. In melanoma, switching from proliferative to invasive states has been associated with melanoma progression and metastasis[18,19] This phenotype switching resembles an EMT-like behaviour, the connection with tumour-initiating abilities in melanoma remains elusive[20,21]. WNT11-FZD7-DAAM1 activates Rho-ROCK1/2-Myosin II to control tumour-initiating potential, local invasion and distant metastasis formation. We show that the invasive fronts of human primary melanomas are enriched in amoeboid invading and proliferating cells expressing non-canonical Wnt and cancer stem cell markers
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