Gene regulatory network landscape of Group 3/4 medulloblastoma

Joshi, P.; Stelzer, T.; Okonechnikov, K.; Sarropoulos, I.; Sepp, M.; Pour-Jamnani, M. V.; Rademacher, A.; Yamada-Saito, T.; Schneider, C.; Schmidt, J.; Schaefer, P.; Leiss, K.; Bortolomeazzi, M.; Mallm, J.-P.; da Silva, P. B. G.; Statz, B.; Wittmann, A.; Schramm, K.; Blattner-Johnson, M.; Fiesel, P.; Jones, B.; Milde, T.; Pajtler, K.; van Tilburg, C. M.; Witt, O.; Rippe, K.; Korshunov, A.; Jones, D. T. W.; Hovestadt, V.; Northcott, P. A.; Thongjuea, S.; Jaeger, N.; Kaessmann, H.; Pfister, S. M.; Kutscher, L. M.

doi:10.1101/2024.02.09.579680

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bioRxiv · 10.1101/2024.02.09.579680

Gene regulatory network landscape of Group 3/4 medulloblastoma

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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.

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Joshi, P., Stelzer, T., Okonechnikov, K., Sarropoulos, I., Sepp, M., Pour-Jamnani, M. V., Rademacher, A., Yamada-Saito, T., Schneider, C., Schmidt, J., Schaefer, P., Leiss, K., Bortolomeazzi, M., Mallm, J.-P., da Silva, P. B. G., Statz, B., Wittmann, A., Schramm, K., Blattner-Johnson, M., Fiesel, P., Jones, B., Milde, T., Pajtler, K., van Tilburg, C. M., Witt, O., Rippe, K., Korshunov, A., Jones, D. T. W., Hovestadt, V., Northcott, P. A., Thongjuea, S., Jaeger, N., Kaessmann, H., Pfister, S. M., Kutscher, L. M.. 2024-02-10. Gene regulatory network landscape of Group 3/4 medulloblastoma. https://doi.org/10.1101/2024.02.09.579680

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