Single-Cell Transcriptomics in Medulloblastoma Reveals Tumor-Initiating Progenitors and Oncogenic Cascades during Tumorigenesis and Relapse

Publication date: Available online 29 August 2019Source: Cancer CellAuthor(s): Liguo Zhang, Xuelian He, Xuezhao Liu, Feng Zhang, L. Frank Huang, Andrew S. Potter, Lingli Xu, Wenhao Zhou, Tao Zheng, Zaili Luo, Kalen P. Berry, Allison Pribnow, Stephanie M. Smith, Christine Fuller, Blaise V. Jones, Maryam Fouladi, Rachid Drissi, Zeng-Jie Yang, W. Clay Gustafson, Marc RemkeSummaryProgenitor 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.Graphical Abstract
Source: Cancer Cell - Category: Cancer & Oncology Source Type: research