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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 Sep 16;36(3) :302-318.e7
PMID: 31474569 PMCID: PMC6760242
AbstractProgenitor 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.
Notes1878-3686 Zhang, Liguo He, Xuelian Liu, Xuezhao Zhang, Feng Huang, L Frank Potter, Andrew S Xu, Lingli Zhou, Wenhao Zheng, Tao Luo, Zaili Berry, Kalen P Pribnow, Allison Smith, Stephanie M Fuller, Christine Jones, Blaise V Fouladi, Maryam Drissi, Rachid Yang, Zeng-Jie Gustafson, W Clay Remke, Marc Pomeroy, Scott L Girard, Emily J Olson, James M Morrissy, A Sorana Vladoiu, Maria C Zhang, Jiao Tian, Weidong Xin, Mei Taylor, Michael D Potter, S Steven Roussel, Martine F Weiss, William A Lu, Q Richard R01 NS072427/NS/NINDS NIH HHS/United States R01 NS075243/NS/NINDS NIH HHS/United States R01 NS078092/NS/NINDS NIH HHS/United States R37 NS096359/NS/NINDS NIH HHS/United States Journal Article United States Cancer Cell. 2019 Sep 16;36(3):302-318.e7. doi: 10.1016/j.ccell.2019.07.009. Epub 2019 Aug 29.