High cellular plasticity state of medulloblastoma local recurrence and distant dissemination

Hailong Liu; Jing Zhang; Ziwei Wang; Wei Wang; Dongming Han; Xuan Chen; Yu Su; Jiao Zhang; Craig Daniels; Olivier Saulnier; Zeyuan John Wang; Chunyu Gu; Fei Liu; Kaiwen Deng; Dongyang Wang; Zhaoyang Feng; Yahui Zhao; Yifei Jiang; Yu Gao; Zijia Liu; Mingxu Ma; Yanong Li; Zitong Zhao; Hongyu Yuan; Youliang Sun; Yanfeng Shi; Tao Yang; Wenxing Li; Xueling Qi; Zejun Duan; Junping Zhang; Mingshan Zhang; Chunjiang Yu; Wei Jin; Xinguang Yu; Yu Tian; Shuaicheng Li; Chunde Li; Michael D Taylor; Jiankang Li; Yong-Qiang Liu; Xiaoguang Qiu; Tao Jiang

doi:10.1016/j.xcrm.2024.101914

High cellular plasticity state of medulloblastoma local recurrence and distant dissemination

Cell Rep Med. 2025 Jan 6:101914. doi: 10.1016/j.xcrm.2024.101914. Online ahead of print.

Authors

Hailong Liu¹, Jing Zhang², Ziwei Wang³, Wei Wang⁴, Dongming Han⁵, Xuan Chen⁵, Yu Su⁶, Jiao Zhang⁷, Craig Daniels⁷, Olivier Saulnier⁸, Zeyuan John Wang⁹, Chunyu Gu¹⁰, Fei Liu¹¹, Kaiwen Deng¹¹, Dongyang Wang¹², Zhaoyang Feng¹¹, Yahui Zhao¹³, Yifei Jiang¹⁴, Yu Gao¹⁵, Zijia Liu⁵, Mingxu Ma², Yanong Li², Zitong Zhao¹⁶, Hongyu Yuan¹⁶, Youliang Sun¹⁷, Yanfeng Shi¹⁸, Tao Yang¹⁹, Wenxing Li²⁰, Xueling Qi¹⁰, Zejun Duan¹⁰, Junping Zhang¹⁰, Mingshan Zhang¹⁰, Chunjiang Yu¹⁰, Wei Jin²¹, Xinguang Yu²¹, Yu Tian⁶, Shuaicheng Li²², Chunde Li¹², Michael D Taylor⁷, Jiankang Li²³, Yong-Qiang Liu²⁴, Xiaoguang Qiu²⁵, Tao Jiang²⁶

Affiliations

¹ Department of Radiotherapy, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China; Beijing Neurosurgical Institute, Beijing 100070, China; China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China; Chinese Institute for Medical Research, Beijing 100069, China.
² Department of Radiotherapy, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China.
³ BGI-Shenzhen, Shenzhen, Guangdong 518083, China.
⁴ Laboratory of Tumor Immunology, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China.
⁵ BGI-Shenzhen, Shenzhen, Guangdong 518083, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
⁶ School of Public Health, Capital Medical University, Beijing 100069, China.
⁷ Cancer and Hematology Center, Texas Children's Hospital, Houston, TX 77002, USA; Department of Pediatrics-Hematology/Oncology and Neurosurgery, Baylor College of Medicine, Houston, TX 77002, USA; The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, ON M5G 1, Canada; The Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 1, Canada.
⁸ Genomics and Development of Childhood Cancers Lab, Institute Curie, PSL University, 75005 Paris, France; Cancer Heterogeneity Instability and Plasticity, Institute Curie, PSL University, 75005 Paris, France.
⁹ Departments of Quantitative Pharmacology and Pharmacometrics (QP2), Merck & Co., Inc., West Point, PA 19486, USA.
¹⁰ Sanbo Brain Hospital Capital Medical University, Beijing 100093, China.
¹¹ Department of Radiotherapy, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China; Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China.
¹² Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China.
¹³ China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China; Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China.
¹⁴ University of Michigan-Shanghai Jiao Tong University Joint Institute, Shanghai Jiao Tong University, Shanghai 200240, China; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA.
¹⁵ Prosper High School, Public School in Prosper, Prosper, TX 75078, USA.
¹⁶ State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
¹⁷ Institute of Basic Medicine, School of Medicine, Tsinghua University Beijing 100084, China.
¹⁸ China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China.
¹⁹ China National GeneBank, BGI-Research, Shenzhen, Guangdong 518083, China.
²⁰ OE Biotech, Shanghai 201114, China.
²¹ The First Medical Center, Chinese PLA General Hospital, Beijing 100039, China.
²² Computer Science Department, City University of Hong Kong, Kowloon, Hong Kong.
²³ BGI-Shenzhen, Shenzhen, Guangdong 518083, China. Electronic address: [email protected].
²⁴ Research Center of Chinese Herbal Resource Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China. Electronic address: [email protected].
²⁵ Department of Radiotherapy, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China; Beijing Neurosurgical Institute, Beijing 100070, China. Electronic address: [email protected].
²⁶ Beijing Neurosurgical Institute, Beijing 100070, China; China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China; Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China. Electronic address: [email protected].

PMID: 39809264
DOI: 10.1016/j.xcrm.2024.101914

Abstract

Medulloblastoma (MB), a heterogeneous pediatric brain tumor, poses challenges in the treatment of tumor recurrence and dissemination. To characterize cellular diversity and genetic features, we comprehensively analyzed single-cell/nucleus RNA sequencing (sc/snRNA-seq), single-nucleus assay for transposase-accessible chromatin sequencing (snATAC-seq), and spatial transcriptomics profiles and identified distinct cellular populations in SHH (sonic hedgehog) and Group_3 subgroups, with varying proportions in local recurrence or dissemination. Local recurrence showed higher cycling tumor cell enrichment, whereas disseminated lesions had a relatively notable presence of differentiated subsets. Chromosomal alteration evaluation revealed distinct genetic subclones during MB progression, such as chr7q gain and chr11 loss in Group_3 disseminations. A subpopulation termed "high cellular plasticity (HCP)" emerged during MB progression and was associated with increased dividing potential and chromatin accessibility, contributing to recurrence. Inhibiting HCP-associated markers, like protein tyrosine phosphatase receptor type Z1 (PTPRZ1), efficiently suppressed MB progression in preclinical models. These findings address critical gaps in understanding the cellular diversity, chromosomal alterations, and biological dynamics of recurrent MB, offering potential therapeutic insights.

Keywords: PTPRZ1; cellular plasticity; medulloblastoma; recurrence and dissemination.