A new study on the origin and development of pediatric tumours of the cerebellum, such as medulloblastoma, has concluded that these tumours are a disorder of early brain development. A TFRI-funded study team found that the cells of these tumours remain very similar to the cells in the part of the brain from which they originate. The authors say this provides the best explanation today about why there is a high incidence of these tumours in childhood.
Led by researchers at the Hospital for Sick Children, the study helps to shed light on how best to develop targeted therapies – currently lacking -- for these tumours as well as improve diagnostics. Studying these tumours has been difficult because there are massive changes in the early development of the cerebellum and accessing it inside the skull is not easy to do.
However, large-scale, single-cell RNA sequencing made it possible for the team identify a “cellular scaffold” for cerebellar development in which the transcriptomes of the distinct (cell) hierarchies can be determined at various points in time and, subsequently, compared to the transcriptomes of childhood cerebellar tumours.
Using this approach in mouse models, the team studied more than 60,000 cells from five embryonic time points and four early post-natal time points (see the diagram) and was able to identify different clusters of cells developed at various times – some during early development, some mid-development, some later and some across all time points.
“Different childhood tumours transcriptionally mirror specific clusters in defined cerebellar lineages. Many of these lineages are only detected over a defined period of development, whereas others persist throughout adulthood,” wrote the study team in Nature (May 2019).
The first author of the study is PhD candidate Maria C. Valdoiu and Dr. Michael D. Taylor is senior study author. Many other TFRI scientists studying brain cancers at numerous pan-Canadian centres contributed to the study.
Two key findings of the team’s research are that the tumours remain very similar to the cells from which they originate and that there are defined temporal windows during which those cell populations are permissive to malignant transformations. For example, the team found that Group 4 medulloblastoma transcriptionally resemble a dual potential progenitor cell population that gives rise to two types of glutamatergic neurons, explaining some of the biology of these tumours.
This work opens the door to understanding more about how normal cells become cancerous and how therapies can be targeted to these cancerous cells. “Now that we better understand when and from which populations these tumours arise, we can strive to direct therapies towards stalling or differentiating the cancerous cells rather than providing non-specific therapies,” says Valdoiu.
The team says their findings can also help to develop clinically relevant mouse models.
Childhood cerebellar tumours mirror conserved fetal transcriptional programs
Maria C. Vladoiu, Ibrahim El-Hamamy, Laura K. Donovan, Hamza Farooq, Borja L. Holgado, Yogi Sundaravadanam, Vijay Ramaswamy, Liam D. Hendrikse, Sachin Kumar, Stephen C. Mack, John J. Y. Lee, Vernon Fong, Kyle Juraschka, David Przelicki, Antony Michealraj, Patryk Skowron, Betty Luu, Hiromichi Suzuki, A. Sorana Morrissy, Florence M. G. Cavalli, Livia Garzia, Craig Daniels, Xiaochong Wu, Maleeha. A. Qazi, Sheila K. Singh, Jennifer A. Chan, Marco A. Marra, David Malkin, Peter Dirks, Lawrence Heisler, Trevor Pugh, Karen Ng, Faiyaz Notta, Eric M. Thompson, Claudia L. Kleinman, Alexandra L. Joyner, Nada Jabado, Lincoln Stein and Michael D. Taylor.
This work was supported in part by funding from TFRI to Michael D. Taylor.