December 1, 2022 -- A multinational team of scientists has used single-cell profiling of freshly isolated human fetal tissue to reveal a reference map of the cell states of the most common malignant childhood brain cancer.
Efforts to understand the most aggressive subgroup-3 form of the pediatric brain cancer medulloblastoma have been impeded by significant differences between humans and mice. The human cerebellum, a small part of the brain near the back of the head, has 750 times as much surface area as that of a mouse. Because the human cerebellum has more types of progenitor cells that help the brain grow during pregnancy, the development process can go wrong in ways that are impossible to elucidate by studying mice.
The limitations of mice in the context of research into human cerebellum development drove an international team led by scientists at Cincinnati Children's Hospital Medical Center to study fetal tissue. In an article published November 30 in the journal Nature, the researchers describe how single-cell profiling of freshly isolated human fetal cerebella created a map of the hierarchical cellular states in medulloblastomas, detailing growth steps down to changes at the single-cell level.
Through the analysis, the team identified a unique transitional cerebellar progenitor connecting neural stem cells to neuronal lineages in developing fetal cerebella. Further intersectional analysis showed that the transitional progenitors were enriched in aggressive medulloblastoma subgroups, including in subgroup-3 and metastatic tumors. Single-cell multiomics found underlying regulatory networks in the transitional progenitor populations, including transcriptional determinants correlated with clinical prognosis.
The result is an integrated single-cell atlas of human fetal cerebella and medulloblastomas that shows potential cell populations predisposed to transformation and regulatory circuitries underlying tumor cell states and oncogenesis. The previously unrecognized transitional progenitor intermediates are predictive of disease prognosis and potential therapeutic vulnerabilities.
New ways to treat medulloblastomas could emerge from the work, which suggests fetal brains can grow too many cells with excess activation of a potential cancer-causing gene called MYC. Targeting the transitional progenitor regulators inhibited MYC expression and the growth of subgroup-3 cancer driven by the gene. The Cincinnati Children's researchers have begun trying to identify small molecules that can target the pathways.
While the Nature paper focuses on medulloblastoma, the researchers see opportunities to use the atlas as a vital resource for brain research to understand other conditions, as Qing Richard Lu, PhD, scientific director of the Brain Tumor Center at Cincinnati Children's, explained.
"The new atlas will help accelerate understanding of other conditions that result from disruptions in healthy early brain development, such as autism, attention deficit-hyperactivity disorder, and developmental dyslexia, and pediatric cerebellar damage," Lu said in a statement.