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

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 Remke; Scott L Pomeroy; Emily J Girard; James M Olson; A Sorana Morrissy; Maria C Vladoiu; Jiao Zhang; Weidong Tian; Mei Xin; Michael D Taylor; S Steven Potter; Martine F Roussel; William A Weiss; Q Richard Lu

doi:10.1016/j.ccell.2019.07.009

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. Epub 2019 Aug 29.

Authors

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

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: xuelian.he@childrens.harvard.edu.
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: richard.lu@cchmc.org.

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Brain Neoplasms
Cell Line, Tumor
Cell Proliferation / genetics
Cell Transformation, Neoplastic / genetics*
Cell Transformation, Neoplastic / pathology
Child, Preschool
Datasets as Topic
Disease Models, Animal
Female
Gene Expression Regulation, Neoplastic*
Gene Knockdown Techniques
Gene Regulatory Networks
Hedgehog Proteins / metabolism
Humans
Male
Medulloblastoma / genetics*
Medulloblastoma / mortality
Medulloblastoma / pathology
Mice, Transgenic
Neoplasm Recurrence, Local / genetics*
Neoplasm Recurrence, Local / pathology
Neoplastic Stem Cells / pathology*
Neuroglia / pathology*
Oligodendrocyte Transcription Factor 2 / genetics
Oligodendrocyte Transcription Factor 2 / metabolism
Prognosis
RNA-Seq
Signal Transduction / genetics
Single-Cell Analysis
Survival Analysis
Transcriptome

Substances

Hedgehog Proteins
OLIG2 protein, human
Olig2 protein, mouse
Oligodendrocyte Transcription Factor 2

Abstract

Publication types

MeSH terms

Substances

Grants and funding