Understanding what is driving tumor development and growth

Although likely representing tumor-driving events, we do not know why or how these genetic changes cause tumor formation. However, this knowledge is essential for understand tumor biology.

Embryonal brain tumors and ependymomas arise from progenitor cells during brain development, although we are still determining the precise cell-of-origin and timing for each of these entities. Consequently, the tumors resemble more the immature progenitor cells than mature neurons or glia, and we need to understand what keeps these cells growing and prevents them from differentiating. Hence, we need to investigate the tumor specific genetic changes in the context of these immature progenitor cells. Brain organoids, or “mini-brains in a Petri dish” provide an ideal in vitro model for this research question. By using different protocols, the brain organoids can mimic in 3D the various steps of normal brain development of different regions of the central nervous system, including the cerebral cortex and the cerebellum. By using reprogrammed healthy cells from a patient and targeted gene manipulation, we are able to imitate what happens in each individual patient and follow the formation of a tumor. We can then analyze these genetically engineered brain tumor organoids at different stages of their development using state-of-the-art technologies. For instance, we can determine how tumor cells change over time and differ from normal progenitors by single cell sequencing and lineage tracing. We can also compare how different mutations lead to different tumors and identify the precise cell-of-origin. Together, these experiments will provide a unique window in the early events of tumor development