Glial Origin and Signaling in Medulloblastoma

Summary of Proposed Research Medulloblastoma (MB) represents the most common malignant childhood brain tumor. Despite aggressive multimodal therapy, the prognosis for many MB patients is grim: nearly half succumb to the disease following tumor recurrence, generally a fatal event for these patients. This presents an urgent need for novel therapeutic modalities that target the relapse-initiating cells and their growth at the root of tumor recurrence, and improve patient survival while minimizing adverse side effects. By using single-cell analysis of MB tumor tissues, we identify a population of transit-amplifying progenitors expressing Olig2, which marks glial progenitors and oligodendroglial precursor cells during neural development, as a prominent tumor-initiating/propagating population during the early phase of MB tumorigenesis. Strikingly, OLIG2 expression is upregulated in relapsed tumors in animal models of sonic hedgehog (SHH)-MB after chemotherapy and human recurrent MBs, suggesting a potential role for glial progenitors and their underlying fate determinants in MB tumor recurrence. Although acquisition of the neuronal progenitor identity is critical for SHH-driven MB formation, which could reflect growth or progression, the contribution of glial progenitor cells during tumor recurrence remains elusive. We hypothesize that a population of glial progenitors are intermediate progenitors predisposed to the transformation before transition to neuronal progenitors in MB initiation and recurrence, and that glial specification factors-mediated core regulatory pathway are a hitherto undiscovered MB tumor-promoting cues that may serve as a potential therapeutic target for MB recurrence. Given that glial progenitors may represent a novel tumor-initiating cell in malignant and recurrent MB, in this proposal, we will dissect tumor heterogeneity, evolution, and microenvironment during tumor recurrence and test the hypothesis that glial progenitors are critical transit-amplifying cells that initiate tumor recurrence. In addition, we will define signaling mechanisms and characterize glial fate determinants-mediated regulatory circuits that drive MB recurrence through genetic and pharmacological approaches. Thus, these proposed studies should advance our understanding of the cells of origin for tumor recurrence and underlying pathogenesis at molecular and cellular levels, and facilitate devising new, effective strategies to treat these deadly pediatric brain cancers.