The discovery of adult CMS stem cells and the development of mouse models have provided strong support for the transformation of CNS stem/precursor cells to gliomas by a series of genetic lesions. One of these changes is hyper-activation of the epidermal growth factor receptor (EGFR). The EGFR gene can be amplified and in addition, gliomas can express mutated EGFR's. The most common of these mutations is EGFRvlll, which has a constitutively activated kinase that activates PI3K, JNK and ERKs. Another glioma- associated change is loss of the tumor suppressor PTEN, which encodes a phosphatidylinositol phosphate phosphatase that opposes PI3K signaling. These clinical observations lead to the overall goal of this proposal. We will analyze how EGFRvlll expression and loss of PTEN alter cell signaling and tumorigenicity. These studies will take advantage of PTEN transgenic mouse models and EGFRvlll-bearing retroviruses. We will use precursor cells from the subventricular zone (SVZ) for these studies since we have extensive knowledge and experience with these cells, and they may be the origin of gliomas. Our preliminary data show that precursor cells with both EGFR expression and PTEN loss form tumors in nude mice. Furthermore, two cultures prepared from these tumors (tumor-conditioned) are karyotypic clones with enhanced tumor-forming potency and decreased capacity to differentiate. Our model is that EGFRvlll expression and PTEN loss transform the precursor cells, and the resulting chromosomal instability allows selection of aggressive, karyotypic clones.
Aim 1 is to determine whether PTEN acts as a suppressor or feedback loop of EGFRvlll signaling. Such a feedback loop might retard tumor progression caused by increased receptor tyrosine kinase signaling (e.g., EGFRvlll).
Aim 2 is examine the mechanism by which EGFRvlll expression and PTEN loss leads to centrosome amplification as well as chromosomal instability.
Aim 3 is to characterize tumor-conditioned cultures and determine whether there is a consistent pattern in which conditioned cells are more potent for tumor formation. These experiments will provide a basic understanding of how these genetic lesions interact and synergize to form tumors. These experiments will provide a basis for future development of new therapies and drugs to prevent tumor progression.
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