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.,Amoeboid cells are associated with melanoma invasive capacity.,Here, the authors show that the WNT11-FZD7-DAAM1 pathway regulates tumour-initiating potential, invasion and metastasis lead by amoeboid cells in the invasive front of melanoma tumours.
In this study, Yue et al. describe a therapeutic strategy termed “targeted chemotherapy” that involves depleting PP2A or inhibiting it using a small molecule inhibitor, phendione, in drug-resistant melanoma.,The authors show phendione induces DNA damage response without causing DNA breaks or inducing cellular dormancy, therefore blocking tumor growth of BRAF mutant and NRAS mutant melanomas.,The emergence of drug resistance is a major obstacle for the success of targeted therapy in melanoma.,Additionally, conventional chemotherapy has not been effective as drug-resistant cells escape lethal DNA damage effects by inducing growth arrest commonly referred to as cellular dormancy.,We present a therapeutic strategy termed “targeted chemotherapy” by depleting protein phosphatase 2A (PP2A) or its inhibition using a small molecule inhibitor (1,10-phenanthroline-5,6-dione [phendione]) in drug-resistant melanoma.,Targeted chemotherapy induces the DNA damage response without causing DNA breaks or allowing cellular dormancy.,Phendione treatment reduces tumor growth of BRAFV600E-driven melanoma patient-derived xenografts (PDX) and diminishes growth of NRASQ61R-driven melanoma, a cancer with no effective therapy.,Remarkably, phendione treatment inhibits the acquisition of resistance to BRAF inhibition in BRAFV600E PDX highlighting its effectiveness in combating the advent of drug resistance.