Midkine as a novel prognostic and therapeutic target in meningioma: insights from single-cell analysis and organoid-based drug validation

Background: Recurrent meningiomas lack effective treatments beyond surgery and radiotherapy, necessitating novel prognostic biomarkers and therapeutic targets. Methods: Single-cell RNA sequencing coupled with the Scissor algorithm, along with bulk transcriptomic analysis, was used to identify recurrence-associated genes in meningiomas. Clinical prognostic value was assessed using WB, ELISA, and IHC. Functional validation involved MDK knockdown and pharmacological inhibition with iMDK in IOMM-Lee and CH157 meningioma cells. Multiplex immunofluorescence staining was used to verify immune cell infiltration. Meningioma organoids were generated to evaluate the efficacy of iMDK. Results: MDK, a key gene of recurrence-associated subclusters, is significantly overexpressed in recurrent meningiomas. Plasma MDK levels are markedly elevated in patients with recurrence propensity. IHC confirmed higher MDK expression in recurrent cases, which, after adjusting for confounding factors, correlates with shorter progression-free survival. Knockdown and iMDK administration reduced proliferation and clonogenicity in IOMM-Lee and CH157 meningioma cells. Additionally, high-MDK meningiomas exhibited immunosuppressive features, including reduced CD8⁺/CD4⁺ T-cell infiltration. Furthermore, iMDK induced structural disintegration of meningioma organoids and cell death. Conclusions: MDK is a key recurrence marker and participates in meningioma progression, promoting proliferation and immunosuppression. Targeting MDK effectively inhibits tumor growth and induces organoid disintegration, highlighting its therapeutic potential.