When Good Things Go Off TRK: The Intersection of Neurodevelopment and Oncology

The elegant and well-orchestrated molecular players responsible for normal neurodevelopment harbor the capacity for detrimental repercussions if mis-expressed at the wrong time, or in the wrong place. With a background in developmental neuroscience and subsequent training in cancer biology, I have long been interested the brain's capacity for change. Combining these distinct yet overlapping fields, my lab utilizes genetic mouse models to explore both normal and abnormal plasticity and the link between these processes in tumors of the central nervous system (CNS). By exploring the role of neurotrophins (a family of proteins important for brain function) and their receptors in development, I hope to gain a better understanding of what makes certain cancers grow so that we can figure out how we might develop novel therapeutics. I am particularly interested in how various neurotrophic and genetic factors can influence the development, survival, and behavior of various cell types within and outside the CNS in normal development and more importantly how these processes can be hijacked in cancer. Important for establishing the developing nervous system, this family of proteins (called the neurotrophin receptors) is very tightly regulated at the DNA, RNA, and protein level. Recent work from our group has shown that a particular change at the RNA level results in a unique variation of a neurotrophin receptor called tropomyosin receptor kinase B, or TrkB. This particular TrkB variant is expressed at very high levels in adult and pediatric cancers, including brain tumors. Forced expression of this receptor causes multiple cancer types in our mouse model, suggesting that it is both a marker and driver of oncogenesis – and a potentially druggable target, highlighting the importance of investigating splice variants in basic and translational research.

Learning Objectives:

1. Summarize the neurotrophin family of receptors and their roles in neurodevelopment and oncology.

2. Explain the role alternative splicing in gliomas, using TrkB.T1 as an example.

3. Review the importance of studying alternative splicing in normal development and pediatric & adult cancers.