Gene regulatory network landscape of Group 3/4 medulloblastoma

Cell-state plasticity drives heterogeneity in Group 3/4 medulloblastoma Abstract Cellular heterogeneity in Group 3 and Group 4 medulloblastomas is a major driver of therapeutic intractability. Here, we describe transcription factor-driven mechanisms underlying cellular diversity in these tumors using a comprehensive single-nucleus multi-omics atlas. Our analysis reveals that rather than fixed entities, these tumors exist along a continuum of cell states defined by four molecular identity axes. We show that perturbing transcription factor activity drives cellular plasticity, a key contributor to tumor heterogeneity. Strikingly, modulation of the lineage determinant PAX6 redirects tumor cells along both Group 3- and Group 4-like differentiation trajectories, modeling a bi-lineage medulloblastoma, and reduces aggressiveness of MYC-driven tumor models. Together, our findings reveal how oncogenic signals co-opt cerebellar unipolar brush cell programs to rewire tumor cell states and identify cellular plasticity as a potential targetable vulnerability in medulloblastoma. Competing Interest Statement CMvT: Alexion, Bayer, Roche and Novartis (Advisory boards); Eli Lilly (Travel Support); Ipsen (Lecture Honoraria); BioMed Valley Discoveries and Day One Biopharmaceuticals (Research Grant) SMP and DTWJ: Heidelberg Epignostix (Founders) TM: Ipsen (Advisory Board) Footnotes ↵§ These authors jointly supervised this study In this version of the manuscript, we have added functional wet-lab validations of key claims derived from the computational work. We have also generated new TF binding data of key TFs in primary patient samples. We have also streamlined the manuscript to focus on cellular plasticity. Funder Information Declared Subject Area - Biochemistry (17746) - Bioengineering (13928) - Bioinformatics (42066) - Biophysics (21499) - Cancer Biology (18650) - Cell Biology (25579) - Clinical Trials (138) - Developmental Biology (13409) - Ecology (19947) - Epidemiology (2067) - Evolutionary Biology (24374) - Genetics (15633) - Genomics (22557) - Immunology (17775) - Microbiology (40505) - Molecular Biology (17217) - Neuroscience (88796) - Paleontology (667) - Pathology (2845) - Pharmacology and Toxicology (4836) - Physiology (7664) - Plant Biology (15179) - Synthetic Biology (4304) - Systems Biology (9839) - Zoology (2272)