OLIG2-Expressing Progenitors May Initiate Medulloblastoma Tumor Formation

Tumorigenesis and recurrence of medulloblastoma (MB) are believed to be driven by a small population of tumor-initiating cells, but these cells have not been well characterized. Using single-cell transcriptomics on tumors from a mouse model of Sonic Hedgehog (SHH)-MB, one of the four MB subtypes, Zhang, He, and colleagues discovered a hierarchy of neural lineage development in SHH-MB. Using pseudo-time analysis to correlate gene expression with developmental stage uncovered the developmental trajectory, revealing that levels of the early neural/glial lineage marger Olig2 characterized the stem-like progenitor population. OLIG2⁺ cells were present and appeared to be the primary cell type propagating at the MB initiation stage, and expression of OLIG2 in a mouse MB model revealed that OLIG2 is tumorigenic. In an analysis of transcriptomic data from a human MB cohort, OLIG2 expression was associated with decreased overall survival in SHH-MB but not in the other three types of MB (WNT-MB, Group 3 MB, and Group 4 MB). Elimination of OLIG2⁺ progenitor cell populations in the mouse MB model inhibited MB growth, implying that the OLIG2⁺ cells are important for tumor initiation, and Olig2 knockout reduced MB growth. However, in late-stage MB tumors, the OLIG2⁺ cells appeared quiescent and constituted a rare subpopulation. In a patient-derived xenograft model using mice transplanted with human SHH-MB cells, OLIG2⁺ cells exhibited a resurgence in treatment-resistant tumors, indicating that this cell population, rare in full-blown tumors, may underlie recurrence following therapy. Transcriptome profiling and genome-wide chromatin immunoprecipitation sequencing experiments revealed that OLIG2 altered the chromatin landscape and served as a hub in a network regulating tumor-cell proliferation and stem-like character. Notably, OLIG2′s activation of Hippo–YAP/TAZ signaling promoted MB growth, and inhibition of both Hippo signaling and AURORA-A/MYCN signaling, also activated by OLIG2, slowed MB progression. Together, these results provide insight into the developmental hierarchy in SHH-MB, suggesting that OLIG2⁺ progenitor cells initiate tumor growth and remain quiescent in full-blown MB, where they may initiate recurrence following treatment if not eliminated.

Zhang L, He X, Liu X, Zhang F, Huang LF, Potter AS, et al. Single-cell transcriptomics in medulloblastoma reveals tumor-initiating progenitors and oncogenic cascades during tumorigenesis and relapse. Cancer Cell 2019 Aug 29 [Epub ahead of print].

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