Synergistic inhibition of NUDT21 by secretory S100A11 and exosomal miR‐487a‐5p promotes melanoma oligo‐ to poly‐metastatic progression

Although early diagnosis and therapeutic advances have transformed the living quality and outcome of cancer patients, the poor prognosis for metastatic patients has not been significantly improved. Mechanisms underlying the complexity of metastasis cannot be simply determined by the straightforward ‘cause‐and‐effect relationships’. We have developed a ‘dry‐lab‐driven knowledge discovery and wet‐lab validation’ approach to embrace the complexity of cancer and metastasis. We have revealed for the first time that polymetastatic (POL) melanoma cells can utilize both the secretory protein pathway (S100A11–Sec23a) and the exosomal crosstalk (miR‐487a‐5p) to transfer their ‘polymetastatic competency’ to the oligometastatic (OL) melanoma cells, via synergistic co‐targeting of the tumor‐suppressor Nudt21. The downstream deregulated glycolysis was verified to regulate metastatic colonization efficiency. Further, two gene sets conferring independent prognosis in melanoma were identified, which have the potential for clinical translation and merit future clinical validation. The metastatic microenvironment involves cooperation between cancer and noncancer cells. This study focused on secretory protein (S100A11–Sec23a) and exosomal (miR‐487a‐5p) pathways in OL and POL melanoma cells. POL cells transfer polymetastatic competency to OL cells, which switch phenotype. Nudt21 targeting relieves the inhibition of glycolysis. Gene sets aid prognosis, showcasing the approach's clinical relevance.