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The ingrained capacity of melanoma cells to rapidly evolve toward an aggressive phenotype is manifested by their increased ability to develop drug-resistance, evident in the case of vemurafenib, a therapeutic-agent targeting BRAF V600E . Previous studies indicated a tight correlation between heightened melanoma-associated macroautophagy/autophagy and acquired Vemurafenib resistance. However, how this vesicular trafficking pathway supports Vemurafenib resistance remains unclear. Here, using isogenic human and murine melanoma cell lines of Vemurafenib-resistant and patient-derived melanoma cells with primary resistance to the BRAF V600E inhibitor, we found that the enhanced migration and invasion of the resistant melanoma cells correlated with an enhanced autophagic capacity and autophagosome-mediated secretion of ATP. Extracellular ATP (eATP) was instrumental for the invasive phenotype and the expansion of a subset of Vemurafenib-resistant melanoma cells. Compromising the heightened autophagy in these BRAF V600E inhibitor-resistant melanoma cells through the knockdown of different autophagy genes (ATG5, ATG7, ULK1), reduced their invasive and eATP-secreting capacity. Furthermore, eATP promoted the aggressive nature of the BRAF V600E inhibitor-resistant melanoma cells by signaling through the purinergic receptor P2RX7. This autophagy-propelled eATP-dependent autocrine-paracrine pathway supported the maintenance and expansion of a drug-resistant melanoma phenotype. In conclusion, we have identified an autophagy-driven response that relies on the secretion of ATP to drive P2RX7-based migration and expansion of the Vemurafenib-resistant phenotype. This emphasizes the potential of targeting autophagy in the treatment and management of metastatic melanoma.

Currently, it is widely acknowledged that a proactive anticancer immunosurveillance mechanism takes part in the rejection of neoplastic lesions before they progress towards a benign or malignant tumour. However in cases of very aggressive neoplastic lesions consisting of cells with high mutational diversity, cancer cell variants might be formed that are capable of evading host defence systems against uncontrolled proliferation and anticancer immunosurveillance. This is mainly accomplished through the exhibition of low immunogenicity, which is a particularly important stumbling block in the revival of long-lasting as well as stable anticancer immunity. Recently, it has emerged emphatically that inciting a cancer cell death routine, associated with the activation of danger signalling pathways evoking emission of damage-associated molecular patterns (DAMPs), markedly increases the immunogenicity of dying cancer cells. This cell death pathway has been termed "immunogenic cell death" (ICD). In the present review we introduce this concept and discuss its characteristics in detail. We also discuss in detail the various molecular, immunological and operational determinants of ICD.