Neurodevelopmental principles underlying pediatric brain cancer

• Applicant: Lena Kutscher, Ph.D.
• Subject Area: Developmental Neurobiology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 551030459

Pediatric brain tumors are the leading cause of cancer-related death in children. Among these, medulloblastoma, an embryonal tumor arising in the developing cerebellum, is one of the most common malignant pediatric brain tumors. Different types of medulloblastoma arise from different progenitor cell populations within the cerebellum. Unfortunately, our understanding of the genetic and molecular basis of medulloblastoma is often hindered by the lack of knowledge underlying normal neural differentiation of these progenitor types. I will address this gap for the Group 3/4 subtypes of medulloblastoma, which arise following aberrant development of a type of bipotent progenitor cell. We will gain a deeper molecular understanding of how these progenitor cells develop normally in the cerebellum and how pediatric tumor cells take advantage of these developmental programs to drive tumorigenesis. In this Emmy Noether proposal, I will test the hypothesis that two conserved transcription factors, LMX1A and TBR2, modulate differentiation of bipotent progenitor cells, and that the same developmental pathways required in these progenitor cells are hijacked during medulloblastoma formation. I will investigate this hypothesis across three main Aims: Aim 1. Determine how cerebellum development is disrupted in the absence of key transcription factors. Aim 2. Resolve the function of key transcription factors and their downstream targets. Aim 3. Investigate how differentiation is derailed during malignant transformation. I will use concepts derived from developmental neuroscience, functional genomics, and cancer research to understand progenitor differentiation in normal development and in disease. Because the principles behind progenitor differentiation are likely conserved across the brain, this research may be broadly applicable to development of other brain regions, human neurodevelopmental disorders, and other pediatric cancers.

• DFG Programme: Emmy Noether Independent Junior Research Groups