Spatiotemporal role of GLI2 in driving SHH-medulloblastoma tumorigenesis
Year: 2026
Type: article
Abstract: BACKGROUND: Medulloblastoma (MB) is a malignant cerebellar tumor primarily affecting children. SHH MB with GLI2 amplification is associated with a particularly poor prognosis. Although GLI2 amplification is clinically recognized, its role in driving SHH-MB remains unclear. METHODS: We generated novel mouse models of GLI2-amplified MB to investigate the role of GLI2 in driving tumorigenesis and assessed their similarity to human tumors using immunohistological and scRNA-seq analyses. Additionally, we examined the spatiotemporal window of tumor development using our mouse models and explored the mechanisms underlying the susceptibility of embryonic cerebellar granule cell progenitors (GCPs) to GLI2-induced tumorigenesis through scRNA-seq analysis. We further investigated the involvement of MAPK pathway in GLI2-driven tumorigenesis and progression by genetically disrupting the pathway. RESULTS: We demonstrate that GLI2 is a primary oncogenic driver in SHH-MB, with its overexpression driving embryonic Math1+ progenitor cells to form SHH-MB. The resulting GLI2-driven tumors closely resemble human GLI2-amplified SHH-MB cellularly and molecularly. Additionally, we determined that embryonic Math1+ GCPs at E13.5-E15.5 are the most susceptible to tumor initiation with GLI2 overexpression alone. In postnatal Math1+ GCPs, additional Trp53 inactivation is required for GLI2-induced tumor formation. scRNA-seq analysis reveals MAPK pathway enrichment in embryonic GCPs and GLI2-driven tumors. Functional studies show that knocking down MEK1/2 in Math1+ progenitor cells or GLI2-driven MB cells prevents tumorigenesis and tumor progression, respectively. CONCLUSIONS: Our studies uncover the developmental origins and molecular mechanisms underlying GLI2-amplified SHH-MB. We also reveal that the MAPK pathway plays a critical role in GLI2-driven SHH-MB tumorigenesis and progression.
Source: Neuro-Oncology
Authors: Najiba Murad, Zhenhua Xu, Jiao Zhang, Xiao Liu, Prathibhani Ramawickrama, Ran Tao, Samuel Rivero-Hinojosa, Melanie Schoof, Ulrich Schüller, Qingshi Chen, Brian R Rood, Roger Packer, Lakshmi Ramachandran Nair, Marina Grachtchouk, Andrzej Dlugosz, Jianhua Yang, Michael D Taylor, Huadong Pei, Yanxin Pei
Institutions: Children's National, Baylor College of Medicine, Texas Children's Hospital, St. Jude Children's Research Hospital, University Medical Center Hamburg-Eppendorf, Kinderkrebs-Zentrum Hamburg, University Cancer Center Hamburg, Purdue University West Lafayette, University of Michigan, U-M Rogel Cancer Center, Dan L Duncan Comprehensive Cancer Center, Georgetown University Medical Center, Georgetown Lombardi Comprehensive Cancer Center, George Washington University
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7130384787