Jayamohan, S.; Venkata, P. P.; Johnson, J. D.; Subramani, B.; Abdelfattah, N. E.; Zou, Y.; Lai, Z.; Hernandez, S. A.; Subbarayalu, P.; Pratap, U. P.; Zheng, S.; Rao, M. K.; Brenner, A. J.; Viswanadhapalli, S.; Vadlamudi, R. K.; Yun, K.; Nair, H. B.; Sareddy, G. R.

Medulloblastoma (MB), the most common malignant pediatric brain tumor, remains associated with high recurrence rates and substantial treatment-related morbidity despite aggressive multimodal therapy. Here, we identify midkine (MDK), a secreted growth factor/cytokine, as a previously unrecognized central regulator of MB growth and survival. Tissue microarray analysis revealed elevated MDK protein expression in MB specimens, and single-cell RNA sequencing datasets showed tumor cell-specific MDK expression. Genetic depletion or antibody-mediated neutralization of MDK suppressed proliferation and survival and induced apoptosis across multiple MB cell lines, whereas recombinant MDK supplementation exerted the opposite effect. Mechanistically, phosphokinase profiling and immunoblot analyses showed that MDK signals through multiple receptors, including nucleolin (NCL), LRP1, and syndecan 2 (SDC2), to sustain oncogenic ERK1/2 and Akt-mTOR-S6 signaling. Transcriptomic profiling following MDK silencing or depletion revealed marked suppression of ribosome biogenesis, global protein translation, and MYC-driven programs, coupled with activation of inflammatory and apoptotic responses. Consistently, mechanistic studies utilizing RPS6 staining, ribosomal RNA quantification, puromycin SUnSET, and OPP incorporation assays confirmed that loss of MDK impairs ribosome biogenesis and protein synthesis. Notably, MDK suppression also triggered robust activation of the IFN-cGAS-STING pathway, linking translational stress to innate immune signaling. In orthotopic xenograft models, CRISPR-mediated MDK knockout significantly reduced tumor growth and prolonged survival. Together, these findings establish MDK as a key integrator of oncogenic signaling, translational control, and innate immunity in MB, highlighting MDK as a compelling therapeutic target.