| Literature DB >> 31474569 |
Liguo Zhang1, Xuelian He2, Xuezhao Liu1, Feng Zhang3, L Frank Huang1, Andrew S Potter1, Lingli Xu4, Wenhao Zhou5, Tao Zheng6, Zaili Luo1, Kalen P Berry1, Allison Pribnow7, Stephanie M Smith7, Christine Fuller1, Blaise V Jones8, Maryam Fouladi1, Rachid Drissi1, Zeng-Jie Yang9, W Clay Gustafson10, Marc Remke11, Scott L Pomeroy12, Emily J Girard13, James M Olson13, A Sorana Morrissy14, Maria C Vladoiu15, Jiao Zhang15, Weidong Tian3, Mei Xin1, Michael D Taylor15, S Steven Potter1, Martine F Roussel7, William A Weiss10, Q Richard Lu16.
Abstract
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.Entities:
Keywords: AURORA-A/MYCN; HIPPO-YAP/TAZ; OLIG2; OPC-like; glial progenitors; medulloblastomas; progenitor heterogeneity; recurrent tumors; single-cell transcriptomics; sonic hedgehog (SHH) signaling
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Year: 2019 PMID： 31474569 PMCID： PMC6760242 DOI： 10.1016/j.ccell.2019.07.009
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743