Genomic tumor evolution dictates human medulloblastoma progression
Ruchiy Y, Tsea I, Preka E, Verhoeven BM, Olsen TK, Mei S, Sinha I, Blomgren K, Carlson LM, Dyberg C, Johnsen JI, Baryawno N. Neurooncol Adv. 2024 Oct 5;6(1):vdae172. doi: 10.1093/noajnl/vdae172. PMID: 39659836; PMCID: PMC11629688.
Background: Medulloblastoma (MB) is the most common high-grade pediatric brain tumor, comprised of 4 main molecular subgroups-sonic-hedgehog (SHH), Wnt, Group 3, and Group 4. Group 3 and Group 4 tumors are the least characterized MB subgroups, despite Group 3 having the worst prognosis (~50% survival rate), and Group 4 being the most prevalent. Such poor characterization can be attributed to high levels of inter- and intratumoral heterogeneity, making it difficult to identify common therapeutic targets.
Methods: In this study, we generated single-cell sequencing data from 14 MB patients spanning all subgroups that we complemented with publicly available single-cell data from Group 3 patients. We used a ligand-receptor analysis tool (CellChat), expression- and allele-based copy-number variation (CNV) detection methods, and RNA velocity analysis to characterize tumor cell-cell interactions, established a connection between CNVs and temporal tumor progression, and unraveled tumor evolution.
Results: We show that MB tumor cells follow a temporal trajectory from those with low CNV levels to those with high CNV levels, allowing us to identify early and late markers for SHH, Group 3, and Group 4 MBs. Our study also identifies SOX4 upregulation as a major event in later tumor clones for Group 3 and Group 4 MBs, suggesting it as a potential therapeutic target for both subgroups.
Conclusions:Taken together, our findings highlight MB’s inherent tumor heterogeneity and offer promising insights into potential drivers of MB tumor evolution particularly in Group 3 and Group 4 MBs.
