Precursor cell-niche interactions and the genesis of brainstem gliomas

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DESCRIPTION (provided by applicant): Brainstem gliomas are a heterogenous group of tumors whose biological behavior depends upon anatomical location. Gliomas of the brainstem comprise 15-20% of brain tumors in children. The majority of these are diffusely infiltrative gliomas of the ventral pons, a devastating cancer that occurs in school age children (peak at age 7) and almost invariably results in death. In dramatic contrast, gliomas occurring in the dorsal pons, midbrain or medulla are classically indolent and carry an excellent prognosis. This sharp anatomic and pathological division between gliomas of the ventral pons (diffuse intrinsic pontine glioma) and those occurring dorsally suggests dysregulation of an underlying cellular or microenvironmental process that is yet to be defined. I hypothesize that pediatric ventral pontine gliomas arise via specific dysregulation of a postnatal precursor cell, microenvironmental niche, or both. In support of this hypothesis, preliminary studies identify a novel population of neural precursor cells in the human ventral pons during childhood. We have also generated the first available cell culture of a human ventral pontine glioma and have isolated from the tumor a neural stem-like cell type. This represents a major advance in the study of this tumor, which has been limited to date by a dearth of tissue available for research and no experimental model system. The proposed experimental plan outlines a systematic evaluation of the normal human and mouse brainstem for stem, lineage-restricted precursor and glial cell populations in the ventral-dorsal axis, as well as a similarly systematic examination of ventral-dorsal differences in the signaling microenvironment of the postnatal brainstem, and finally testing the functional significance of identified candidate signaling pathways and a putative cell of origin in diffuse intrinsic pontine glioma cells. Techniques employed will include fluorescent immunohistochemistry and confocal microscopy, immuno-laser capture microdissection, cell culture, transplantation studies, FACS, gene expression microarray analysis, single cell PCR and genetic cell fate mapping. I am a neurologist who completed PhD training in neuroscience; my thesis project explored microenvironmental determinants of postnatal hippocampal neural precursor cell fate. I am now completing a fellowship in neuro-oncology, and focusing my future research efforts on postnatal developmental mechanisms in brain tumor pathophysiology. This proposed research plan draws upon my background in postnatal stem and precursor cell biology, and offers the critical opportunity to develop and hone the molecular biology skills necessary for my successful transition to independence in the field of developmental neuroscience. My mentor Dr. Beachy and Co-Mentor Dr Rowitch will provide an ideal environment to develop such skills and to immerse myself in the study of developmental signaling biology in brain cancer. I will receive both didactic and hands-on training in numerous molecular techniques and will be surrounded by the technological and intellectual support to succeed. PUBLIC HEALTH RELEVANCE: Brainstem gliomas of childhood account for up to 20% of pediatric brain tumors, are frequently fatal and are poorly understood. By studying the normal brainstem during childhood, this project seeks to identify the cell of origin and molecular factors that may result in the growth of these devastating tumors. We will test the functional significance of the findings about the normal brainstem in brainstem tumor cells, which may ultimately result in new therapies for this tragic disease.