Individuals with neurofibromatosis type 1 (NF1) carry mutations in the NF1 tumor suppressor gene and develop benign peripheral nerve sheath tumors called neurofibromas which can transform to malignant peripheral nerve sheath tumors (MPNST). Neurofibromas contain normal nerve constituents: axons, Schwann cells, fibroblasts, and mast cells, and aberrant Schwann cells free of axons. Tumorigenesis results from complete loss of function at NF1, as neurofibromas and MPNST are characterized by biallelic mutations in tumor Schwann cells, with other cell types recruited secondarily. We developed mouse model systems for neurofibroma formation in NF1, and also performed large scale gene expression array analyses to identify candidate genes relevant to neurofibroma formation. We also identified a candidate EGFR+ tumor-initiating cell in human and mouse neurofibromas which forms spheres in vitro, can multi-lineage differentiate and form neurofibroma-like lesions in vivo. In this application, we propose to use unique mouse models and the neurofibroma sphere-formation system to test the relevance of this putative tumor-initiating cell to neurofibroma formation. We will also further define markers of the tumor-initiating cells for prospective isolation and to target the cells therapeutically. Finally, we will define molecules necessary for neurofibroma Schwann cell and for putative tumor-initiating cell survival. Together these studies will identify cellular and molecular underpinnings of tumor formation in the nervous system, and identify therapeutic targets for the treatment of NF1.
Neurofibromatosis type 1 is one of the most common of all human inherited human disorders, and NF1 patients develop neurofibromas, tumors associated with peripheral nerves, which cause disfigurement and morbidity. Individuals with plexiform neurofibroma can develop MPNST, a lethal sarcoma which is the leading cause of death in adults with NF1. The goal of this project is to use the mouse models and tumor-initiating cell models to test the relevance of molecules we identified through gene expression analysis to neurofibroma formation. Molecules identified as relevant to tumorigenesis in our model systems will not only provide mechanistic insight into neurofibroma formation but also be targets for therapeutic trials in human NF1 patients.
|Brundage, M E; Tandon, P; Eaves, D W et al. (2014) MAF mediates crosstalk between Ras-MAPK and mTOR signaling in NF1. Oncogene 33:5626-36|
|Wu, J; Patmore, D M; Jousma, E et al. (2014) EGFR-STAT3 signaling promotes formation of malignant peripheral nerve sheath tumors. Oncogene 33:173-80|
|Prada, Carlos E; Jousma, Edwin; Rizvi, Tilat A et al. (2013) Neurofibroma-associated macrophages play roles in tumor growth and response to pharmacological inhibition. Acta Neuropathol 125:159-68|
|Jessen, Walter J; Miller, Shyra J; Jousma, Edwin et al. (2013) MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors. J Clin Invest 123:340-7|
|Wu, Jianqiang; Dombi, Eva; Jousma, Edwin et al. (2012) Preclincial testing of sorafenib and RAD001 in the Nf(flox/flox) ;DhhCre mouse model of plexiform neurofibroma using magnetic resonance imaging. Pediatr Blood Cancer 58:173-80|
|Mayes, Debra A; Rizvi, Tilat A; Cancelas, Jose A et al. (2011) Perinatal or adult Nf1 inactivation using tamoxifen-inducible PlpCre each cause neurofibroma formation. Cancer Res 71:4675-85|
|Miller, S J; Lan, Z D; Hardiman, A et al. (2010) Inhibition of Eyes Absent Homolog 4 expression induces malignant peripheral nerve sheath tumor necrosis. Oncogene 29:368-79|
|Johansson, Gunnar; Mahller, Yonatan Y; Collins, Margaret H et al. (2008) Effective in vivo targeting of the mammalian target of rapamycin pathway in malignant peripheral nerve sheath tumors. Mol Cancer Ther 7:1237-45|
|Wu, Jianqiang; Williams, Jon P; Rizvi, Tilat A et al. (2008) Plexiform and dermal neurofibromas and pigmentation are caused by Nf1 loss in desert hedgehog-expressing cells. Cancer Cell 13:105-16|
|Williams, Jon P; Wu, Jianqiang; Johansson, Gunnar et al. (2008) Nf1 mutation expands an EGFR-dependent peripheral nerve progenitor that confers neurofibroma tumorigenic potential. Cell Stem Cell 3:658-69|
Showing the most recent 10 out of 46 publications