Mary Clare Beytagh

Medulloblastoma is the most common malignant brain tumor in children. Twenty to 30 percent of patients will present with metastasis, the major cause of morbidity and mortality in patients. We develop human iPSC-derived mouse models and perform in vivo CRISPRi screens to identify and investigate drivers and suppressors of medulloblastoma growth and metastasis with the aim of developing new targeted therapies.

Medulloblastoma (MB) is the most common malignant brain tumor in children. Metastatic dissemination is the major cause of morbidity and mortality in patients, and approximately 20 to 30 percent of patients present with metastatic disease. Among MB subgroups, Group 3 MB is the most likely to present with metastatic disease, has the poorest overall prognosis, there are no targeted therapies for either the primary or metastatic compartment. We have developed a human iPSC derived neuroepithelial stem (NES) cell-based orthotopic mouse model for Group 3 MB. To functionally define mediators of Group 3 MB tumorigenesis and metastasis, we performed a genome-wide in vivo CRISPRi screen in primary MB and metastases using the NES-based model. We identified single-guide RNAs (sgRNAs) that were recurrently enriched in metastatic samples, corresponding to genes that, when knocked down, may promote metastasis. This first-of-its-kind in vivo CRISPRi screen in Group 3 MB reveals novel suppressors of metastasis, investigation of which promises a more robust biological understanding of leptomeningeal dissemination in MB.