Approximately 90 per cent of cases of glioblastoma, a highly malignant and aggressive brain tumour, recur because of the tumour's ability to spread into healthy brain tissue.
Therefore, specifically studying the cells that spread into the normal brain tissue is key to preventing recurrence in the disease.
A new study published in Developmental Cell found that glioblastoma cells hijack normal brain development processes to infiltrate brain tissue, suggesting new ways to control the spread of the cancer.
The study was led by Dr. Federico Gaiti, a scientist at UHN's Princess Margaret Cancer Centre, in collaboration with the team in the lab of Dr. Gelareh Zadeh.
"We found that infiltrating glioblastoma cells — tumour cells that spread into healthy brain tissue — adopt features of early-stage brain cells called oligodendrocyte precursor cells (OPCs)," says Dr. Gaiti, who is also an assistant professor in the Department of Medical Biophysics at the University of Toronto (U of T).
"These cells normally interact with neurons during brain development. Glioblastoma cells mimic them by switching on similar regulatory programs, helping them integrate into brain circuits and spread more effectively."
The team used techniques called single-cell sequencing and spatial transcriptomics to study the regulation of infiltrating glioblastoma cells. By analyzing which genes were active, chemical modifications to the DNA, how open or closed different regions of DNA were, and how tumour cells physically and molecularly interacted with nearby neurons, they identified key developmental pathways that invasive glioblastoma cells hijack to spread through the brain.
One such pathway is called NOTCH signaling — a cell communication system used by multicellular organisms to control cell fate decisions, such as differentiation, proliferation and apoptosis. The tumour cells hijack this pathway to activate oligodendrocyte lineage programs, effectively masquerading as normal OPCs.
The findings suggest that targeting this pathway and the regulatory programs involved may help limit tumour spread.
"We were able to confirm that these programs play a key role in driving the tumour's ability to spread, by disrupting their control of tumour cells' invasive behavior," says Yiyan Wu, one of the first authors of the paper and a PhD student at U of T.
As a next step, the team is conducting experiments to pharmacologically target the pathway and related gene regulatory programs to assess their potential in reducing tumour invasion.
This work was supported by The Princess Margaret Cancer Foundation, Canadian Institutes for Health Research-ICR, Ontario Institute for Cancer Research, Brain Canada Foundation, Cancer Research Society, Terry Fox Research Institute, American Brain Tumor Association, Natural Sciences and Engineering Research Council of Canada, Brain Tumor Foundation of Canada.
