Yuan Zhu Ph.D.'s, research group is interested in understanding molecular and cellular mechanisms underlying the development of normal neural stem and progenitor cells as well as tumorigenesis in the nervous system. We are using the mouse as a model system to develop genetic engineering mouse (GEM) tumor models, which recapitulate human cancers both genetically and phenotypically (Zhu et al., Cell 1998; Zhu et al., Science 2002; Zhu et al., Cancer Cell 2005; Zheng et al., Cancer Cell 2008; Wang et al., Cancer Cell 2009; Wang et al., Cell 2012). Particularly, we have been focusing on the role of tumor suppressor genes in the nervous system.
Neurofibromatosis type 1 (NF1):
In addition to the high risk of developing tumors in the nervous system, approximately 30-70 percent of individuals with NF1 have learning disabilities, representing the most significant cause of lifetime morbidity associated with this disease. Dr. Zhu’s research group is interested in understanding the role of NF1 in developing neural stem and progenitor cells and how its loss causes developmental abnormalities, leading to the structural brain defects associated with severe learning disabilities in humans, and the development of benign peripheral nerve sheath tumor – plexiform neurofibroma in the peripheral nervous system (PNS), and optic pathway glioma in the central nervous system (CNS). Dr. Zhu’s research group is investigating the mechanism underlying these NF1-associated diseases and performing preclinical studies with animal models. Our goal is to integrate basic, translational and clinical research to develop novel preventive and treatment therapies for NF1-associated diseases.
High-grade glioma and glioblastoma (GBM):
NF1 tumor suppressor gene is one of the most frequently mutated genes in GBM – the most frequent and lethal brain cancer in humans. However, the development of GBM in individuals afflicted with NF1 is not common. Using GEM models, we have demonstrated that inactivation of Nf1 is not a robust oncogenic event unless it occurs in the context of p53 loss. Thus, sequential inactivation of tumor suppressor genes p53 and Nf1 is required for effectively transforming neural stem and progenitor cells in the subventricular zone (SVZ) of the lateral ventricle. These studies have established NF1 as a context-dependent tumor suppressor gene in GBM, providing the mechanism by which most individuals with NF1 have no increased risk of developing GBM. We are exploring these mouse models to address: (1) how the tumor suppressor genes p53 and Nf1 regulate growth and transformation of neural stem/progenitor cells in vivo and in vitro, (2) what is the lineage relationship between neural stem and progenitor cells or differentiated cells and GBM in the nervous system, and (3) what is the molecular mechanism(s) underlying the development of astrocytomas/GBM and malignant peripheral nerve sheath tumors (MPNSTs) from normal neural stem and progenitor cells.
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., Guignard, F., Zhao, D., Liu, L., Burns, D. K., Mason, R. P., Messing, A. 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.
Zheng, H.*, Chang, L.*, Patel, N., Yang, J., Lowe, L., Burns, D.K. and Zhu, Y. (2008). Induction of abnormal proliferation by nonmyelinating Schwann cells triggers neurofibroma formation. Cancer Cell, 13:117-128 (*Co-first author).
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 (*Co-first author). PMCID: PMC2721466.
Wang, Y., Kim, E., Wang, X., Novitch, B.G., Yoshikawa, K., Chang, L.S. and Zhu, Y. (2012). ERK inhibition rescues defects in fate-specification of Nf1-deficient neural progenitors and brain abnormalities. Cell, 150(4):816-830. PubMed PMID: 22901811.
Kim, E., Wang, Y., Kim, S., Bornhorst, M., Jecrois, E.S., Anthony. T.E., Wang, C., Li, Y.E., Guan, J., Murphy, G.G., Zhu, Y (2014). Transient inhibition of the ERK pathway prevents cerebellar developmental defects and improves long-term motor functions in murine models of neurofibromatosis type 1. eLife. 2014 Dec 23;3. doi: 10.7554/eLife.05151. [Epub ahead of print] PubMed PMID: 25535838.
Complete List of Published Work in My Bibliography: