OICR researchers create first-of-its kind atlas of developing mouse brain cells to help find the ‘cell of origin’ for brain and spinal cord tumours
By looking closely at the building blocks of normal brain development, researchers may have pinpointed where glial cancers start, and uncovered clues on how to stop them.
A study led by SickKids’ Dr. Peter Dirks, recently published in Nature Communications, explored the relationship between a primitive type of brain cell called radioglial precursors (RGPs) and the cells of glial tumours, which form in the brain and spinal cord.
Precursor cells are usually present before birth, and RGPs are involved in the early development of the brain. But researchers have observed that RGPs share common traits with certain glial cancer cells and have long suspected that glial cancers may originate from RGPs.
Dirks, PhD candidate Akram Hamed and other collaborators investigated by doing single cell transcriptomics on more than 100,000 brain cells from mice to create a detailed atlas of the developing mouse brain.
“We really zoomed in on precursor cells, which allowed us to see the richness of the diversity within these cells,” says Dirks, who is also Co-Leader of OICR’s Brain Cancer Translational Research Initiative.
From this first-of-its-kind atlas, they classified three types of RGP that had not been identified before: embryonic, juvenile and adult. Then they used an advanced algorithm to compare their mouse brain atlas to single-cell data from more than a hundred human glial cancers.
The comparison showed a significant connection between RGPs at the embryonic stage and certain glial cancer cells, suggesting that glial tumours do in fact arise from these primitive cells.
“Now that we think we’ve discovered the ‘cell of origin’ for glial cancers, we can study what causes that cell to veer off course and become cancer, and potentially develop therapeutics to persuade it to go back down its regular developmental pathway,” says Dr. Lincoln Stein, Head Adaptive Oncology, OICR and a collaborator on the study. Stein’s lab, including PhD candidate Ibrahim El-Hamamy, developed the algorithm that allowed for the mouse-human cell comparison.
Working with Stein and fellow collaborator Professor Benjamin Simons of the University of Cambridge, Dirks and colleagues went on to validate these findings by engineering mutations to embryonic cells in developing mouse brains. Sure enough, the mice went on to develop tumours in adulthood that resembled glioblastoma.
Work on this study continues, with plenty left to learn about the relationship between embryonic precursor cells and brain tumours. There are still competing hypotheses about whether the study’s findings mean that glial cancers originate before we are born, or whether something happens later in life to cause mature cells to ‘walk back’ developmentally to embryonic states.
Dirks and colleagues hope to provide more answers as their research progresses. But what they have learned so far about the types of precursor cells and their relationship with cancer could have major implications for stopping glial cancers in the future.
“When cancers like glioblastoma present, they are so complex that they can often evade our therapies,” Dirks says. “If we understand the mechanisms in normal cells that make them transition to cancer, we might be able to identify patients earlier and stamp out the cancer before it gets too complicated.”