Development and Characterization of Mouse Models of Human Glioblastoma Public Deposited

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  • March 20, 2019
Creator
  • Zhang, Qian
    • Affiliation: School of Medicine, Department of Biochemistry and Biophysics
Abstract
  • Glioblastoma multiforme (GBM) is a very challenging disease clinically because of lacking effective treatments. Accurate and accessible preclinical models of GBM are required to both understand these diseases and facilitate development of diagnostic tests and therapies. Recently, genetic mutations in human gliomas are better understood and techniques to generate genetically engineered mice (GEM) are more sophisticated, which makes it possible to mimic those mutations in the mouse in an accurate way. Here, we developed mouse models of human GBM by simulating most common genetic mutations in human GBMs, including abnormal RTK-Ras signal, Rb pathway, and Pten locus. In the beginning, the model was manipulated so that the mutation (K-RasG12D) was transferred to astrocytes using an hGFAP-Cre allele, which resulted in primary GBMs. This model is valuable for understanding the role of K-Ras overactivation in primary GBM's formation and cell-oforigin. However, developmental phenotypes other than GBM in this model restrict its further uses in mechanistic studies and combinations with other mutations. In subsequent models, we modified the strategy and generated an inducible system, in which genetic changes can be spatially and temporally induced in adult astrocytes, thus avoiding developmental defects. Induction is elicited by activation of CreERtam, expressed from the human GFAP promoter, after intraperitoneal 4OH-tamoxifen injection. With high penetrance and reproducible timing, the combination of all three events induces tumors that possess all common histological features of human GBM, including brain invasion, high mitotic indexes, angiogenesis, and necrosis. Furthermore, analysis of event combinations provides insight into disease etiology. For example, without Pten inactivation, pRb inactivation and K-Ras activation predispose to high-grade astrocytic tumors that lack the necrotic phenotype characteristic of GBM. Neither activation of K-Ras nor inactivation of Pten alone produces detectable pathology, and thus are involved in tumor progression. In contrast, inactivation of pRb function initiates disease that does not progress to high-grade tumors. Because of their inducibility, high-penetrance and molecular and histological similarity to human high-grade astrocytomas, these models are extremely promising for both further mechanistic analyses and for preclinical studies, including the validation of potential drug targets and diagnostic and therapeutic development.
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  • Van Dyke, Terry A.
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