Identifying Molecular Mechanisms and Cellular Origins of Cancers of the Nervous System

Cancers of the nervous system are the most common type of solid tumors among children. They are a heterogeneous population of benign and malignant tumors that growth within the central or peripheral nervous system. The molecular mechanisms governing onset and progression, and the cellular origins of these cancers remain intense areas of research. We created mouse models that develop multiple tumors in both the central and peripheral nervous systems. We deleted Pten and activated K-ras using Cre-lox technology driven by the mouse GFAP promoter. Our models develop benign neurofibromas that progress to malignant peripheral nerve sheath tumors, optic nerve tumors, and malignant brain gliomas. We find that loss of the PTEN tumor suppressor is critical in the onset and progression of these tumors. In addition, we show that 18F-fluorodeoxyglucose positron emission tomography can distinguish peripheral nerve sheath tumors as benign or malignant, and is an effective modality to monitortherapeutic response to multi-kinase inhibitors. Furthermore, we establish a new cell-of-origin in malignant brain gliomas. We deleted Pten and activated K-ras in adult neural stem cells of the mouse brain and performed developmental tracing analysis to determine where in the neurogenic niche tumors initiated. We show that gliomas initiate from a region called the subcallosal zone (SCZ), the caudal extension of the subventricular zone (SVZ). We find that progenitors in the SCZ transform prior to those in the SVZ, and that the cellular compositions in each region are uniquely affected by our genetic manipulation. These results reveal a critical role of the SCZ in gliomagenesis. As such, these studies define a novel molecular mechanism in the progression of peripheral nerve sheath tumors, and propose a new cell-of-origin in brain gliomas