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Zhang L, He X, Liu X, Zhang F, Huang LF, Potter AS, Xu L, Zhou W, Zheng T, Luo Z, Berry KP, Pribnow A, Smith SM, Fuller C, Jones BV, Fouladi M, Drissi R, Yang ZJ, Gustafson WC, Remke M, Pomeroy SL, Girard EJ, Olson JM, Morrissy AS, Vladoiu MC, Zhang J, Tian W, Xin M, Taylor MD, Potter SS, Roussel MF, Weiss WA, Lu QR
Single-Cell Transcriptomics in Medulloblastoma Reveals Tumor-Initiating Progenitors and Oncogenic Cascades during Tumorigenesis and Relapse
Cancer Cell (2019) 36:302-318.e7.
Progenitor heterogeneity and identities underlying tumor initiation and relapse in medulloblastomas remain elusive. Utilizing single-cell transcriptomic analysis, we demonstrated a developmental hierarchy of progenitor pools in Sonic Hedgehog (SHH) medulloblastomas, and identified OLIG2-expressing glial progenitors as transit-amplifying cells at the tumorigenic onset. Although OLIG2(+) progenitors become quiescent stem-like cells in full-blown tumors, they are highly enriched in therapy-resistant and recurrent medulloblastomas. Depletion of mitotic Olig2(+) progenitors or Olig2 ablation impeded tumor initiation. Genomic profiling revealed that OLIG2 modulates chromatin landscapes and activates oncogenic networks including HIPPO-YAP/TAZ and AURORA-A/MYCN pathways. Co-targeting these oncogenic pathways induced tumor growth arrest. Together, our results indicate that glial lineage-associated OLIG2(+) progenitors are tumor-initiating cells during medulloblastoma tumorigenesis and relapse, suggesting OLIG2-driven oncogenic networks as potential therapeutic targets.
Publication Date: 2019-09-16.
PMCID: PMC6760242
Last updated on Thursday, June 04, 2020