p53, Rb and Ras Pathways in Neural Stem Cell Homeostasis and Transformation

University Of California, San Francisco, San Francisco CA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Despite recent advances in therapy and surgery, glioblastomas remain one of the most deadly tumor types and can affect both children and adults with devastating survival rates. Effective therapies have been elusive due to the heterogeneous neuronal population within a typical brain tumor, making it hard to define and target the cell population responsible for propagation of the tumor. Recently, several research groups have identified cancer stem cells in human brain tumors. These cells are exclusively CD133+ and have the capacity for self-renewal as well as the ability to phenotypically recapitulate the primary tumor they were harvested from. However, it is still unclear if these tumor stem cells arise directly from the neural stem (NS) cell compartments in the brain and what genetic changes occur to allow stem cells to become tumorigenic. We have developed a mouse model that allows us to activate genes of interest in an inducible and specific manner in NS cells utilizing the soxl promoter. We will utilize this system to functionally test the hypothesis that brain tumors can develop directly from the NS cell compartments of the adult brain and to evaluate the role pathways commonly mutated in glioblastomas play in NS cell homeostasis and transformation; (1) develop an inducible NS cell specific expression system in the adult mouse; (2) evaluate the requirement of p52, Rb, and Ras in maintaining NS cell homeostasis, and (3) develop a brain tumor model based on NS cell specific disruption of the p53, RB, and Ras pathways. With the discovery of a stem cell niche within brain tumors, it becomes crucial to track if transformed NS cells are the source for tumor development versus reversion of differentiated cells to a stem cell like state. Relevance: A better understanding of the development of glioblastomas will help in the design of cancer therapies directed specifically at inhibiting the cancer stem cell population within brain tumors. Complete eradication of the tumor maintenance cells will decrease the chance of tumor recurrence often seen in brain cancers, thereby increasing survival rates for patients afflicted with malignant tumors. [unreadable] [unreadable] [unreadable]