Midkine inhibits dormancy of disseminated melanoma cells

Tirado, C. A. R.; Riaz, T. A.; Rodrigues, A. A.; Kale, N.; Satheeshkumar, S. J.; Perez-Gallegos, A.; Olmeda, D.; Soengas, M. S.; Sosa, M. S.

doi:10.1101/2025.05.27.656365

bioRxiv · 10.1101/2025.05.27.656365

Midkine inhibits dormancy of disseminated melanoma cells

Tirado, C. A. R.·Riaz, T. A.·Rodrigues, A. A.·Kale, N.·Satheeshkumar, S. J.·Perez-Gallegos, A.·Olmeda, D.·Soengas, M. S.·Sosa, M. S.

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Abstract

A major challenge in melanoma treatment is the emergence of aggressive metastases from previously dormant disseminated cancer cells (DCCs). Here we identify Midkine (MDK) as a key factor that disrupts melanoma DCC dormancy by triggering an autocrine signal that suppresses the dormancy inducer NR2F1 and alters the p-p38/p-ERK ratio, via ALK signaling. Dormant melanoma DCCs in lymph nodes and visceral tissues exhibit an MDKLOW/NR2F1HIGH phenotype. Transient NR2F1 activation for one month with a potent agonist counteracts MDK-driven mTORC1 activity and suppresses lung metastasis in mice bearing human melanoma DCCs. Dual targeting of MDK (genetic blockade) and NR2F1 (activation) markedly limits metastatic outgrowth and extends survival for 6 months in mouse models independent of BRAF status. These findings support the MDK-NR2F1 axis as a promising therapeutic target to sustain dormancy and prevent melanoma recurrence. Statement of SignificanceThis work identifies Midkine as a key disruptor of tumor dormancy in melanoma, driving metastatic awakening via NR2F1 suppression. Dual targeting of Midkine (inhibition) and NR2F1 (activation) prolongs survival in preclinical models.

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Tirado, C. A. R., Riaz, T. A., Rodrigues, A. A., Kale, N., Satheeshkumar, S. J., Perez-Gallegos, A., Olmeda, D., Soengas, M. S., Sosa, M. S.. 2025-05-31. Midkine inhibits dormancy of disseminated melanoma cells. https://doi.org/10.1101/2025.05.27.656365

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