2. Academic Validation
  3. Single-Cell Transcriptomics in Medulloblastoma Reveals Tumor-Initiating Progenitors and Oncogenic Cascades during Tumorigenesis and Relapse

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. doi: 10.1016/j.ccell.2019.07.009.
Liguo Zhang 1,  Xuelian He 2,  Xuezhao Liu 1,  Feng Zhang 3,  L Frank Huang 1,  Andrew S Potter 1,  Lingli Xu 4,  Wenhao Zhou 5,  Tao Zheng 6,  Zaili Luo 1,  Kalen P Berry 1,  Allison Pribnow 7,  Stephanie M Smith 7,  Christine Fuller 1,  Blaise V Jones 8,  Maryam Fouladi 1,  Rachid Drissi 1,  Zeng-Jie Yang 9,  W Clay Gustafson 10,  Marc Remke 11,  Scott L Pomeroy 12,  Emily J Girard 13,  James M Olson 13,  A Sorana Morrissy 14,  Maria C Vladoiu 15,  Jiao Zhang 15,  Weidong Tian 3,  Mei Xin 1,  Michael D Taylor 15,  S Steven Potter 1,  Martine F Roussel 7,  William A Weiss 10,  Q Richard Lu 16
Affiliations

Affiliations

  • 1 Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
  • 2 Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; Boston Children's Hospital, Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA. Electronic address: [email protected].
  • 3 Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, Department of Biostatistics and Computational Biology, School of Life Sciences, Fudan University, Shanghai 200433, China.
  • 4 Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Shanghai 201102, China.
  • 5 Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Shanghai 201102, China.
  • 6 State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 7 Tumor Cell Biology Division, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 8 Radiology Division, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
  • 9 Cancer Biology Program, Fox Chase Cancer Center, Temple University Health System, Philadelphia, PA 19111, USA.
  • 10 Department of Neurology, Pediatrics, and Surgery and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94143, USA.
  • 11 Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany.
  • 12 Boston Children's Hospital, Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
  • 13 Division of Pediatric Hematology/Oncology, Fred Hutchinson Cancer Research Center, University of Washington School of Medicine, Seattle Children's Hospital, Seattle, WA 98145-5005, USA.
  • 14 Department of Biochemistry and Molecular Biology, The University of Calgary, Calgary, AB T2N 4N1, Canada.
  • 15 Developmental & Stem Cell Biology Program, The Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada.
  • 16 Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. Electronic address: [email protected].
PMID: 31474569 DOI: 10.1016/j.ccell.2019.07.009
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.

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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