January 2020Research at the Lady Davis Institute

Cellular origins of pediatric brain tumours identified

Several types of highly aggressive and, ultimately, fatal pediatric brain tumours originate during brain development, a researcher at the Lady Davis Institute and her collaborators have discovered.

The genetic event that triggers the disease happens in the very earliest phases of cellular development, most likely prenatal, says Dr. Claudia Kleinman, whose findings have been published in the journal Nature Genetics, and represent a significant advance in understanding these diseases.

“We have determined that stalled development of progenitor cells in the pons and forebrain, where a large proportion of high-grade embryonal and pediatric tumours emerge, is responsible for several childhood brain cancers,” said Dr. Kleinman.

“Rather than developing normally, the cells’ progress is arrested and they transform into malignancies. But they retain many features of the original cells, and we could pinpoint the tumour origins among the hundreds of different cell types present in the brain.”

This is called the Peter Pan Syndrome, as these cells are stuck in time, unable to age, and this is what causes the tumours. The challenge is now to identify how best to unlock these cells, promote their differentiation and allow for normal processes to take over.

Brain tumours are the leading cause of cancer-related deaths in children. For several of these tumours, there are no effective therapies, and survival is often less than two years. Indeed, Dr. Kleinman points out, very limited progress has been made in treating afflicted children.

By applying sophisticated single-cell sequencing techniques and large-scale data analysis, researchers compiled the first comprehensive profile of the normal prenatal pons, a major structure on the upper part of the brainstem that controls breathing, as well as sensations including hearing, taste, and balance.

Dr. Kleinman’s team performed the bioinformatics and established the molecular identity for cell types in this and other brain regions, as well as the dynamics underlying their differentiation.

They created an atlas of more than 65,000 individual cells and defined the developmental dynamics for 191 distinct cell populations. They then mapped patient samples to this atlas and identified the origins of WNT medullo-blastomas, embryonal tumours with multilayered rosettes (ETMRs), and high grade gliomas (HGGs).

“The genesis of the tumours is very early in brain development, which means that there are really no environmental instigators or preventive measures that parents can take,” Dr. Kleinman says. “Advancing our understanding of these tumours is important because the effects are so devastating, we want to bring hope to the patients.”

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