New insights into rare type of brain tumour in children

ETMR affects almost exclusively children under the age of four and, due to its rarity, has been little researched to date. In the current study, eleven tumour samples were examined using modern methods of single-cell RNA sequencing and spatial imaging. Three different malignant cell types were identified – from stem cell-like to intermediate to more differentiated, neuron-like cells. These cell types form a hierarchical structure similar to that of brain development in the embryo.

A key finding of the research team's investigations concerns the so-called C19MC cluster – a group of microRNAs (short RNA molecules that regulate gene activity) located on chromosome 19. This cluster plays an important role in embryonic development but is normally deactivated after birth. However, in over 90 percent of ETMR cases, it is reactivated. The research team was able to show that C19MC is primarily active in stem cell-like tumour cells, where it controls numerous genes that are crucial for cell division and maturation. Importantly, experimental blockade of these microRNAs significantly slows down tumour cell proliferation and induces cell death.

Furthermore, the analysis showed that the different tumour cell types communicate with each other via signalling molecules. More differentiated cells produce growth factors, which in turn stimulate stem cell-like cells to continue dividing. This communication takes place via the FGFR and Notch signalling pathways, among others – two mechanisms that are already being addressed therapeutically in other types of cancer. In laboratory models and tumour samples derived from patients, inhibitors of these signalling pathways were therapeutically active. A five-year-old boy with ETMR who was treated with an FGFR inhibitor as part of an individual case application showed a partial response of the tumour after two months.

"Our systematic analysis at the single-cell level and the link to functional experiments allow us to take a detailed look at the cellular organisation and molecular drivers of ETMR for the first time," says co-first author Lisa Gabler-Pamer from the Department of Neurosurgery at MedUni Vienna, who was working at the Dana-Farber Cancer Institute in Boston at the time of the study and, along with other MedUni Vienna researchers, contributed significantly to the findings. The study provides an in-depth characterisation of the tumour biology of ETMR – from cellular architecture and regulation by microRNAs to the signalling networks within the tumour. Based on this, new approaches for targeted therapies are opening up, which could help to improve the currently very poor prognosis for this disease in the future. Currently, the average survival time of affected children is only around 14 months.

Publication: Nature Cancer
Cellular hierarchies of embryonal tumors with multilayered rosettes are shaped by oncogenic microRNAs and receptor–ligand interactions.
Alexander Beck, Lisa Gabler-Pamer, Gustavo Alencastro Veiga Cruzeiro, Sander Lambo, Bernhard Englinger, McKenzie L. Shaw, Olivia A. Hack, Ilon Liu, Rebecca D. Haase, Carlos A.O. de Biagi Jr., Alicia Baumgartner, Andrezza Do Nascimento Silva, Marbod Klenner, Pia S. Freidel, Jochen Herms, Louisa von Baumgarten, Joerg C. Tonn, Niklas Thon, Katharina Bruckner, Sibylle Madlener, Lisa Mayr, Daniel Senfter, Andreas Peyrl, Irene Slavc, Daniela Lötsch, Christian Dorfer, Rene Geyregger, Nicole Amberg, Christine Haberler, Norman Mack, Benjamin Schwalm, Stefan M. Pfister, Andrey Korshunov, Lissa C. Baird, Edward Yang, Susan N. Chi, Sanda Alexandrescu, Johannes Gojo, Marcel Kool, Volker Hovestadt, Mariella G. Filbin
https://doi.org/10.1038/s43018-025-00964-9