Midkine inhibits dormancy of disseminated melanoma cells

A significant factor in cancer-related mortality in melanoma is the appearance of intrinsically aggressive distal metastases. This recurrence frequently results from the awakening of dormant disseminated cancer cells (DCCs). One of the most puzzling clinical features in this disease is that DCCs rapidly develop into metastases in certain melanoma patients, while remaining inactive in others. We have previously identified NR2F1 as a driver of dormancy, but the mechanisms underlying its regulation, particularly when DCC are "awakened", are poorly understood. This study reveals that the growth factor Midkine (MDK) triggers a potent autocrine mechanism that deactivates NR2F1-dependent dormancy in DCC, ultimately favouring metastatic outgrowth. The effect of MDK was found linked to deregulation of the p-p38/p-ERK ratio in DCCs, in a process that was partly ALK-dependent. Supporting the physiological relevance of these data, MDK and NR2F1 were inversely correlated in DCCs in human lymph nodes (LN). In this regard, we observed that human LN biopsies negative for metastasis carried higher percentages of the dormant MDKLOW/NR2F1HIGH DCC phenotype, an effect that was inverted in metastasis-positive LN. Moreover, activation of NR2F1 with a specific agonist decreased the metastasis-initiating capacity of MDKHIGH DCCs by blocking MDK-driven mTORC1 activity. Dual therapy targeting MDK (via inhibition) and NR2F1 (via activation) markedly improved survival in mouse models of melanoma. This investigation reveals that MDKHIGH melanomas share a mechanism that that disrupts the natural capacity of DCCs to enter dormancy. Moreover, this study suggests that combining an NR2F1 agonist with an MDK inhibitor could be a potential therapeutic strategy to prolong the dormancy phase of melanoma DCCs, thereby preventing metastasis formation.