The UM laboratory is working on an international study that will reveal the origin of pediatric brain tumors

September 21, 2022 —

An international team of researchers has found the first hint that a type of medulloblastoma might be preventable by identifying how and where these tumors develop during the development of the human fetal brain.

Medulloblastoma, an aggressive type of pediatric brain tumor, is present in a premalignant form at birth, having initially developed during the first or second trimester of pregnancy, the study found.

Because medulloblastomas typically appear in childhood, around the age of seven, the team’s discovery is the first hint that there may be a window of several years in which medulloblastoma could be prevented from ever occurring. The results were published today in the renowned journal Nature.

Four leading research groups were partners in the study, including groups at:

• The University of Manitoba (led by Dr. Tamra Werbowetski-Ogilvie, Professor of Biochemistry and Medical Genetics at Max Rady College of Medicine, Investigator at Children’s Hospital Research Institute of Manitoba, and Fellow at CancerCare Manitoba Research Institute);
• The National Cancer Center in Tokyo (led by Dr. Hiromichi Suzuki, Chief Investigator and Principal Investigator in the Department of Translational Brain Cancer Research);
• The Seattle Children’s Research Institute (led by Dr. Kathleen Millen, Professor and Principal Investigator at the Center for Integrative Brain Research);
• The Hospital for Sick Children (SickKids) in Toronto (led by Dr. Michael Taylor, pediatric neurosurgeon and principal investigator in the developmental and stem cell biology program at SickKids and professor of surgery at the University of Toronto).

Brain tumors are the deadliest form of childhood cancer, accounting for 20 percent of all new pediatric cancer cases. Treatment for medulloblastoma currently consists of aggressive surgery, high-dose chemotherapy, and/or total brain and spinal cord radiation. Up to 40 percent of patients still die from the disease, while survivors deal with the long-term toxicities associated with chemotherapy and radiation.

Medulloblastoma consists of several subgroups and the study focused on the most common and least well understood subgroup, called group 4. The aim was to identify how and where group 4 tumors arise during embryonic development.

Researchers collected medulloblastoma samples from children’s hospitals around the world and used multiple sequencing technologies to successfully identify genetic variations that can cause group 4 medulloblastoma.

They found that these genetic variations effectively ‘blocked’ normal cell differentiation in a particular cell type that was present only during early fetal development in the human cerebellum. This “getting stuck” in normal cellular differentiation results in a premalignant form of the tumor, which then persists in the brain after birth, a finding that can be generalized to the other forms of medulloblastoma.

The researchers note that the cell type they have identified is far more common and is found in a region of the developing cerebellum that is structurally more complex in humans than in other mammals. They say that this could mean that medulloblastoma is a direct consequence of the developed complexity of the human cerebellum.

“This project was a beautiful example of teamwork, with each lab contributing an important piece of the puzzle,” said UM’s Werbowetski-Ogilvie. “Working as a team over the past 18 months has taken us in exciting new directions.

“Now that we can pinpoint where these tumors come from, we can develop better models of the disease, which can then be used for large-scale drug testing. This may even allow for earlier detection, so this research is very exciting and opens up many new possibilities.”

Crucially, the team’s findings show that medulloblastomas develop much earlier in pregnancy than previously thought. Doctors may have a window between birth and the onset of symptoms to detect medulloblastomas before they develop and potentially prevent them from developing into deadly brain tumors. This is believed to be the first time that medulloblastoma has been identified as potentially preventable.

This work was supported by the National Institutes of Health, Stand Up To Cancer, Canadian Institutes of Health Research, Fonds de Recherche du Québec – Santé, Natural Sciences and Engineering Research Council of Canada, CancerCare Manitoba Foundation, National Cancer Center Research and Development Funds and SickKids Foundation.

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