Coordinated changes in midkine expression and midkine-associated multiomic profile in glioma microenvironment

Abstract

Abstract Midkine (MDK), a multifunctional growth factor, has been implicated in promoting tumor progression, yet its role in glioblastoma (GBM) remains insufficiently characterized. To investigate MDK’s function in glioma, we integrated four RNA-Seq datasets into a harmonized cohort of 1,017 adult gliomas, including 256 GBM samples. We complemented this with freshly collected human GBM tissues and matched primary cell cultures to evaluate MDK expression and secretion patterns, further contextualized using single-cell RNA-Seq. Finally, we tested the impact of GBM-derived MDK on macrophage secretome composition to validate our in silico observations. We found that MDK expression increases with tumor grade in IDH wildtype gliomas, accompanied by a shift in isoform proportions favoring the canonical MDK transcript. High MDK expression was associated with poor prognosis specifically in GBM, where the MDK high subgroup comprised 75% of cases. MDK high GBMs exhibited a distinctive multiomic signature, including elevated chemokine and cytokine expression. Functionally, GBM-derived MDK induced macrophages to secrete multiple cytokines and chemokines, suggesting its role in reshaping the tumor microenvironment. Our findings reveal MDK’s previously underappreciated role in GBM aggressiveness and immune modulation, underscoring its potential as a biomarker and actionable therapeutic target for most GBM patients.