Single-Cell Transcriptomics in Medulloblastoma Reveals Tumor-Initiating Progenitors and Oncogenic Cascades during Tumorigenesis and Relapse PMID: 31474569

ADC Targets in Oncology

2026-04-10

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

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].

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.