Abstract
Medulloblastoma (MB) is a highly heterogeneous and one of the most malignant pediatric brain tumors, comprising four subgroups: Sonic Hedgehog, Wingless, Group 3, and Group 4. Group 3 MB has the worst prognosis of all MBs. However, the molecular and cellular mechanisms driving the maintenance of malignancy are poorly understood. Here, we employed high-throughput single-cell and bulk RNA sequencing to identify novel molecular features of Group 3 MB, and found that a specific cell cluster displayed a highly malignant phenotype. Then, we identified the glutamate receptor metabotropic 8 (GRM8), and AP-1 complex subunit sigma-2 (AP1S2) genes as two critical markers of Group 3 MB, corresponding to its poor prognosis. Information on 33 clinical cases was further utilized for validation. Meanwhile, a global map of the molecular cascade downstream of the MYC oncogene in Group 3 MB was also delineated using single-cell RNA sequencing. Our data yields new insights into Group 3 MB molecular characteristics and provides novel therapeutic targets for this relentless disease.
Highlights
Medulloblastoma (MB) is one of the most prevalent malignant (WHO IV) brain tumors in children, accounting for 15–20% of pediatric central nervous system tumors [1]
Through detailed analysis of cellular heterogeneity, we identified a specific cell cluster with the tumorigenesis signature of Group 3 MB and interrelated molecular cascades initiated by MYC
We initially selected the MB single-cell RNA sequencing datasets published in the Gene Expression Omnibus (GEO) and included one cohort (GSE119926) of 25 tumor samples and 11 patient-derived xenograft (PDF) models for downstream analysis
Summary
Medulloblastoma (MB) is one of the most prevalent malignant (WHO IV) brain tumors in children, accounting for 15–20% of pediatric central nervous system tumors [1]. Over 40% of patients with MB are diagnosed with metastases, with a grim median survival [2,3,4]. Multimodal therapy, including combination of surgical resection, radiation, and adjuvant chemotherapy, has become a standard for MB, even though approximately one-third of patients with MB die from the disease [5]. The identification of critical regulators that control MB malignance could facilitate the development of more effective therapeutics. Current consensus identifies the existence of four major MB subgroups (Sonic Hedgehog [SHH], Wingless [WNT], Group 3, and Group 4) with different molecular characteristics. Group 3 MB is refractory to intensive multimodal therapy and displays the worst prognosis.
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