Cell and Developmental Biology University of Michigan

Research

Use of mouse genetics to understand the molecular and cellular mechanisms underlying the initiation and progression of tumor development.

During development, a single cell (fertilized egg) undergoes multiple tightly regulated cellular processes including proliferation, differentiation, migration and cell death to ultimately form a functional multicellular organism. A series of studies suggest that parallel processes occur during tumorigenesis. Recent evidence indicates that tumor cells often re-activate and illicitly utilize developmental programs to promote their growth. Thus, to some degree, tumorigenesis can be viewed as development gone awry. My laboratory is interested in studying cancer from a developmental perspective. We employ mouse genetics to develop genetic engineering mouse (GEM) tumor models, which recapitulate human cancer both genetically and phenotypically. In particular, we have generated a series of mouse models for tumors in the nervous system. By employing a germline mutation at the p53 gene and a conditional mutation at the Neurofibromatosis type 1 (NF1) gene, we generated mouse models for astrocytoma and glioblastoma multiforme (GBM) in the central nervous system as well as neurofibroma and malignant peripheral nerve sheath tumor (MPNST) in the peripheral nervous system. We are exploring these mouse models to address: (1) whether neural stem cells or differentiated cells are the cellular targets for tumors in the nervous system and (2) how the tumor suppressor genes regulate growth and transformation of neural stem cells in vivo and in vitro.

Lab Members

• Lou Chang
  Graduate Student
• Yuan Wang
  Graduate Student

Publications

Representative Publications

• Wang, Y.*, Yang, J.*, Zheng, H., Tomasek, G.J., Zhang, P., McKeever, P.E., Lee, E.P. and Zhu, Y. (2009). Expression of mutant p53 proteins implicates a lineage relationship between neural stem cells and malignant astrocytic glioma in a murine model. Cancer Cell, 15(6):514-26. (*These authors contributed equally to this work)
• Zheng, H.*, Chang, L.*, Patel, N., Yang, J., Lowe, L., Burns, D.K. and Zhu, Y. (2008). Induction of abnormal proliferation by non-myelinating Schwann cells triggers neurofibroma formation. Cancer Cell, 13: 117-128 (*These authors contributed equally to this work)
• Joseph, N.M., Mosher, J.T., Buchstaller, J., Snider, P., McKeever, P.E., Lim, M., Conway, S.J., Parada, L.F., Zhu, Y and Morrison, S.J. (2008). The loss of Nf1 transiently promotes self-renewal but not tumorigenesis by neural crest stem cells., Cancer Cell, 13: 129-140
• Romero, M.I., Lu, M., Lush, M.E., Lei, L., Parada L.F. and Zhu, Y. (2007). Deletion of Nf1 in neurons induces increased axon collateral branching after dorsal root injury. Journal of Neuroscience, 27 (8): 2124-2134. 2005
• Parada L.F., Kwon C.H. and Zhu Y. (2005). Modeling neurofibromatosis type 1 tumors in the mouse for therapeutic intervention. Cold Spring Harbor Symposia on Quantitative Biology, 70: 173-6.
• Zhu, Y., Guignard, F., Zhao, D., Liu, L., Burns, D. K., Mason, R. P., and Parada, L. F (2005). Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma. Cancer Cell, 8 (2):119-130.
• Zhu, Y.*, Harada, T., Liu, L., Lush, M.E., Guignard, F., Harada, C., Burns, D.K., Bajenaru, M.L., Gutmann, D.H. and Parada, L.F. (2005). Inactivation of NF1 in CNS causes increased glial progenitor proliferation and optic glioma formation. Development, 132 (24):5577-88 *Corresponding author.
• Gitler, A.D.*, Zhu, Y.*, Ismat, F.A., Lu, M.M., Yamauchi, Y., Parada, L.F. and Epstein, J.A. (2003). The type 1 Neurofibromatosis (Nf1) gene product has distinct and essential roles in neural crest and endothelial cells. Nature Genetics, 33 (1):75-79. (*Both of these authors contributed equally to this work).
• Zhu,Y., Ghosh, P., Charnay, Burns, D.K. and Parada, L.F. (2002). Neurofibromas in NF1: Schwann cell origin and role of tumor environment. Science, 296 (5569):920-922.
• Zhu, Y. and Parada, L.F. (2002).Molecular biology and genetics of neurologic tumors. Nature Reviews Cancer, 2 (8):616-626.
• Zhu,Y., Romero, M., Ghosh, P., Ye, Z., Charnay, P., Rushing, E.J., Marth, J.D. and Parada, L.F. (2001). Ablation of NF1 function in neurons induces abnormal development of cerebral cortex and reactive gliosis in the brain. Genes & Development, 15 (7):859-876.
• Zhu, Y., Richardson, J.A., Parada, L.F. and Graff, J.M. (1998). Smad3 mutant mice develop metastatic colorectal cancer. Cell, 94 (6):703-714.