Tumor cells generate astrocytes that contribute to SHH-driven medulloblastoma relapse

Astrocytes, a major glial cell type in the brain, play a critical role in supporting the progression of medulloblastoma (MB), the most common malignant pediatric brain tumor. By lineage tracing analyses and single cell RNA sequencing, we demonstrate that astrocytes are predominately derived from the transdifferentiation of tumor cells in relapsed MB (but not in primary MB), although MB cells are generally believed to be neuronal-lineage committed. Such transdifferentiation of MB cells relies on Sox9, a transcription factor critical for gliogenesis. Our studies further reveal that bone morphogenetic proteins (BMPs) stimulate the transdifferentiation of MB cells by inducing the phosphorylation of Sox9. Pharmaceutical inhibition of BMP signaling represses MB cell transdifferentiation into astrocytes, and suppresses tumor relapse. Our studies establish the distinct cellular sources of astrocytes in primary and relapsed MB, and provide an avenue to prevent and treat MB relapse by targeting tumor cell transdifferentiation. Overall design: In this study, we used single-cell sequencing to analyze the composition of primary and relapsed medulloblastoma; RNA sequencing to analyze the gene expression of astrocytes in primary and ralapsed medulloblastoma.