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Degrees:
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M.D.,Ph.D.
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Department:
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Neurology
Neurological Surgery
Pediatrics
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Research Center:
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Cancer Center
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Keywords:
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mouse genetics, mouse models, brain tumors, neuroblastoma, myc, gene therapy
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Research Description:
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Our laboratory is broadly interested in developing mouse models which faithfully recapitulate the biology and genetics of human tumors of the nervous system. By targeting human cancer genes to appropriate tissues in transgenic mice, faithful animal models can be created for human cancers. Perhaps surprisingly, few tumors have been modeled in the mouse by recapitulating the most frequently occurring genetic alterations found in human malignancies. Mouse tumors generated in this manner are thought to share many of the same secondary mutations as those found in human malignancies. These models therefore provide a system to
1) identify the subsequent genetic events which promote tumorigenesis,
2) explore the pathophysiology that underlies malignant progression, and
3) develop novel diagnostic and therapeutic modalities for these tumors. Emerging technologies from the human genome project can help facilitate these goals, as these technologies are being developed specifically to analyze complex genetic systems.
We have created transgenic mice that overexpress MYCN in the neural crest and develop neuroblastoma. Analysis of tumor DNA by CGH has demonstrated a region of gain on chromosome 11 that is syntenic with a gain on human chromosome 17, the most common genetic abnormality in human neuroblastoma. We have recently completed a genome wide analysis of microsatellite markers in 24 additional tumors. This analysis confirmed the gain of chromosome 11, and has identified new regions of allelic imbalance on chromosomes 1, 3, 14, and 18. All of these regions are syntenic with regions of LOH in childhood neuroblastoma.
In related experiments, we have found that transgene positive mice of strain FVB/N are resistant to tumor formation, while transgene positive mice of strain 129Sv/J are completely penetrant for tumors. We have set up a screen to identify the germ line modifiers that mediate sensitivity and resistance to tumors.
To identify genes regulated by MYCN, we have made an inducible MYCN expression construct. This construct and a parallel inducible CMYC construct have been introduced into human cells to generate RNA from induced and uninduced cells. In collaboration with Pat Brown's lab at Stanford, these RNA populations have been hybridized to an expression array composed of 19,000 cDNAs identified through the human genome project MYCN specific response genes identified through these experiments are being further characterized.
The Epidermal Growth Factor Receptor gene (EGFR) is commonly amplified or over-expressed in advanced glial malignancies, and in this manner resembles MYCN which is commonly amplified in advanced cases of neuroblastoma. We have created transgenic mice that overexpress v-erbB (the oncogenic homologue of EGFR) using the S100 beta promotor. Six independent founders have developed infiltrating glial neoplasms. Both penetrance and grade of tumors can be increased by further deletion of ink4a/arf, a gene commonly deleted in human gliomas. These animals are being used to identify new genes that contribute to glioma in the mouse, and to develop preclinical therapies.
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Web Page:
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Selected Publications:
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Weiss, W.A., Aldape, K, Burns, M., Kuriyama, H., DePinho, R., Bishop, J. M., and Israel, M. Targeted expression of v-erbB causes oligodendroglioma in transgenic mice. In preparation.
Weiss, W. A., Godfrey, T, Francisco, C., and Bishop, J. M. (2000) Genome wide screen for allelic imbalance in a mouse model for neuroblastoma Cancer Research. 60:2483-2487.
Weiss, W. A., Aldape, K., Mohapatra, G., Feuerstein, B. G., and Bishop, J. M. (1997) Targeted expression of MYCN causes neuroblastoma in transgenic mice. The EMBO J. 16: 2985-2995.
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Prerequisite for student research:
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