Loss of PRC2 function enables progression of medulloblastoma under therapy

Livia Garzia, PhD
Scientist
Research Institute of the McGill University Health Centre 
Cancer Research Program
Centre for Translational Biology

Associate Professor
Department of Surgery
McGill University
Montreal, QC, Canada

This conference is hosted by Frédéric Charron, PhD. This conference is part of the 2025-2026 IRCM conference calendar.

About this conference
Medulloblastoma is the most common malignant pediatric brain tumor and a leading cause of mortality and long-term morbidity in children. Intratumoral and intertumoral heterogeneity render it particularly difficult to treat, especially in infants under three years of age, in whom craniospinal irradiation is contraindicated, resulting in inferior survival outcomes. Using an in vivo genome wide functional mutagenesis screen, we identified recurrent loss of function events converging on the activity of the PRC2 complex. Human tumors and mouse models of refractory or relapsing medulloblastoma displayed loss of H3K27me3, a histone modification associated with PRC2-dependent gene repression. Experimental depletion of H3K27me3 in medulloblastoma model systems triggered de novo enhancer activation, viral mimicry, and an inflamed-but-excluded immune phenotype. Concurrently, H3K27me3 loss activated transcriptional and growth programs consistent with enhanced replication stress tolerance. In vivo, H3K27me3-low cells were resistant to chemotherapy and showed enhanced leptomeningeal dissemination; targeting immunosuppression attenuated metastatic spread. We propose that concurrent disruption of replication stress tolerance and reversal of immune exclusion represents a rational therapeutic strategy to prevent or treat relapse in young medulloblastoma patients.

About Livia Garzia
Dr. Livia Garzia is a Scientist in the Cancer Research Program at the Research Institute of the McGill University Health Centre (The Institute) and an Associate Professor in McGill University’s Department of Surgery. Her research focuses on the molecular mechanisms driving metastasis and therapy resistance in pediatric solid cancers, particularly bone sarcomas and brain tumors.

After completing her PhD in Life Sciences at the Telethon Institute for Genetics and Medicine in Naples, Italy, Prof. Garzia trained in cancer genetics at The Hospital for Sick Children in Toronto. Her team uses functional genomics to identify the genetic and epigenetic factors behind tumor progression and relapse. Recent work has revealed the role of histone mutations in neurodegeneration (Cell, 2023) and the impact of the epigenetic regulator EZHIP in osteosarcoma (Nature Communications, 2025).

She also established Quebec’s largest sarcoma biobank, advancing translational research and redefining how pediatric brain tumors metastasize. Recipient of awards from the FRQS, CIHR and the Nicole et François Angers Sarcoma Research Chair, Prof. Garzia’s research continues to shape the future of pediatric oncology.

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