Researchers using single-cell analysis have gained new insight into the most common type of childhood brain cancer. The team has pinpointed where in the brain one of the four subtypes of the cancer, called medulloblastoma, originates and further characterized another subtype. Their findings promise to impact clinical care for medulloblastoma. They were published 24 July 2019 as an advance online publication in Nature.
“The ability to look at individual cells has propelled us 10 steps forward in our understanding of how the subtypes of medulloblastoma arise, what drives them and how we can make treatments more effective for patients,” said co-senior author Paul Northcott, Ph.D., of St. Jude Children’s Research Hospital in a press release.
Medulloblastoma is classified into four distinct subtypes, two of which (Group 3 and Group 4) are poorly understood. Effective subgroup-specific therapies have yet to emerge despite extensive characterization of the genomic landscapes of the cancer’s subtypes. This suggests that a deeper understanding of the biological and cellular basis of MB is essential. “This is particularly urgent for Group 3 and Group 4 MB, which often bear inferior outcomes,” the authors wrote.
In this study, the team of researchers conducted single-cell RNA sequencing on 25 tumor samples from patients with each of the four subtypes. They used this technique to better understand how genes are controlled, highlighting important mechanisms that can dictate a cell’s behavior. It gave the team a new perspective onhow the subtypes arise and relate to each other.
For example,the results provide for the first time an indication that Group 4 medulloblastoma tumors may arise from cells in the cerebellum called glutamatergic cerebellar nuclei and unipolar brush cells. This is a critical finding for future research into Group 4 medulloblastoma. Understanding the cell of origin may make it possible to develop accurate laboratory models.
The study did not confirm a cell of origin for Group 3 medulloblastoma. However, the results did suggest several possible explanations. For example, Group 3 may arise from tissues outside the cerebellum which were not studied. It is also possible that the oncogene MYC, which characterizes Group 3, alters the cells to make them unrecognizable when compared to their origins. Future studies will focus on understanding more about the origins of Group 3.
“Group 3 and Group 4 medulloblastomas have confounded the field, with some very clearly belonging to one subtype or the other but another group exhibiting the hallmarks of both subtypes,” said co-senior author Mario Suva, M.D., Ph.D., of Massachusetts General Hospital and the Broad Institute of MIT and Harvard in the press release. “Now, we can more clearly see that there is an intermediate group, straddling Group 3 and Group 4 classification.”
The results suggest a new molecular and cellular explanation for the challenges associated with classifying Groups 3 and 4. They also provide a framework for future classifications. In all, the findings of the study, the authors wrote, “will enable future studies to assess translational opportunities and to evaluate the impact of therapeutic approaches on the spectrum of cellular states that drive medullablatoma.”
