ID #810 STAT3-CDK9 Transcriptional Axis Regulates ADAM9 to Promote Aggressive Medulloblastoma

Abstract

Medulloblastoma (MB) is the most common malignant pediatric brain tumor, with Group 3 MB (G3MB) representing the most aggressive subtype and poorest clinical outcomes. Although the oncogenic transcriptional regulator cyclin-dependent kinase 9 (CDK9) is aberrantly activated in G3MB to drive transcriptional elongation, the molecular interactions that integrate transcriptional elongation with oncogenic signaling to sustain gene expression programs and tumor progression remain poorly defined. Here, we identify a functional interaction between activated STAT3 and CDK9 in G3MB and demonstrate that this axis is essential for tumor growth, stemness, and therapeutic resistance. Pharmacologic and genetic inhibition of STAT3 and CDK9 synergistically suppresses G3MB cell proliferation, accompanied by marked induction of apoptotic cell death and downregulation of proliferation and pro-survival associated genes. Combined STAT3/CDK9 inhibition significantly impairs spheroid formation in G3MB patient derived xenograft and reduces expression of stemness associated markers, indicating disruption of tumor-initiating cell properties. Mechanistically, RNA-seq profiling identified A Disintegrin and Metallopeptidase Domain 9 (ADAM9) as a STAT3-CDK9 dependent transcriptional target that amplifies IL-6-gp130 driven feed-forward signaling and promote epithelial–mesenchymal transition and angiogenesis. In Vivo, dual inhibition of STAT3 and CDK9 significantly reduces tumor growth and proliferation in subcutaneous MB xenograft models. Importantly, therapeutic efficacy in orthotopic mouse models further confirmed significant suppression of intracranial G3MB tumor progression. Collectively, these findings identify STAT3-CDK9 signaling as an oncogenic axis in G3MB and provide strong preclinical evidence that co-targeting STAT3 and CDK9 is a promising therapeutic strategy for high-risk pediatric brain tumor, in part by disrupting a STAT3-CDK9-ADAM9 feed-forward circuit that sustains oncogenic signaling.