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The long-term interest of the Ratner research laboratory is to define the interactions between glial cells and axons during nervous system development and how those interactions go awry in disease, with the goal of providing novel therapies to patients with nervous system diseases. Neurofibromatosis type 1 (NF1) is an inherited autosomal dominant disorder (1:3,500 humans) that involves the formation of many nerve-associated tumors and other non-tumor related problems. Neurofibromatosis type 2 (NF2) involves the development of schwannomas, benign tumors composed of Schwann cells (peripheral glial cells). Elucidating the mechanisms by which the nerve-associated tumors arise in both diseases can lead not only to the development of therapy for NF1 and NF2 patients, but also can prove useful in providing information about noninherited nervous system cancers.
Kalamarides M, Acosta MT, Babovic-Vuksanovic D, Carpen O, Cichowski K, Gareth Evans D, Giancotti F, Oliver Hanemann C, Ingram D, Lloyd AC, Mayes DA, Messiaen L, Morrison H, North K, Packer R, Pan D, Stemmer-Rachamimov A, Upadhyaya M, Viskochil D, Wallace MR, Hunter-Schaedle K, Ratner N. Neurofibromatosis 2011: a report of the Children's Tumor Foundation Annual Meeting. Acta Neuropathol. 2011.
Yang, J., Ylipää, A., Sun, Y., Zheng, H., Chen, C., Nykter, M., Trent, J., Ratner, N., Lev, D., and Zhang, W. Genomic and Molecular Characterization of Malignant Peripheral Nerve Sheath Tumor Identifies the IGF1R Pathway as a Primary Target for Treatment. Clin Cancer Res. 2011.
Wood M, Rawe M, Johansson G, Pang S, Soderquist RS, Patel AV, Nelson S, Seibel W, Ratner N, Sanchez Y. Discovery of a small molecule targeting IRA2 deletion in budding yeast and neurofibromin loss in malignant peripheral nerve sheath tumor cells. Mol Cancer Ther. Sep;10(9):1740-50. 2011.
Shang X, Cancelas JA, Li L, Guo F, Liu W, Johnson JF, Ficker A, Daria D, Geiger H, Ratner N, Zheng Y. R-Ras and Rac1 GTPase Crosstalk Regulates Hematopoietic Progenitor Cell Migration, Homing and Mobilization.Biol Chem. 2011 May 13.
Mayes DA, Rizvi TA, Cancelas JA, Kolasinski NT, Ciraolo GM, Stemmer-Rachamimov AO, Ratner N. Perinatal or Adult Nf1 Inactivation Using Tamoxifen-Inducible PlpCre Each Cause Neurofibroma Formation. Cancer Res. 2011 Jul 1;71(13):4675-85.
Wu J, Dombi E, Jousma E, Scott Dunn R, Lindquist D, Schnell BM, Kim MO, Kim A, Widemann BC, Cripe TP, Ratner N. Preclincial testing of Sorafenib and RAD001 in the Nf(flox/flox); DhhCre mouse model of plexiform neurofibroma using magnetic resonance imaging. Pediatr Blood Cancer. Feb, 2011.
Ryan MA, Nattamai KJ, Xing E, Schleimer D, Daria D, Sengupta A, Köhler A, Liu W, Gunzer M, Jansen M, Ratner N, Le Cras TD, Waterstrat A, Van Zant G, Cancelas JA, Zheng Y, Geiger H. Pharmacological inhibition of EGFR signaling enhances G-CSF-induced hematopoietic stem cell mobilization. Nat Med. 16(10):1141-6. Oct, 2010.
Hummel TR, Jessen WJ, Miller SJ, Kluwe L, Mautner VF, Wallace MR, Lázaro C, Page GP, Worley PF, Aronow BJ, Schorry EK, Ratner N. Gene expression analysis identifies potential biomarkers of neurofibromatosis type 1 including adrenomedullin. Clin Cancer Res. 16(20):5048-57. Oct, 2010.
Bosco EE, Nakai Y, Hennigan RF, Ratner N, Zheng Y. NF2-deficient cells depend on the Rac1-canonical Wnt signaling pathway to promote the loss of contact inhibition of proliferation. Oncogene. Apr 29;29(17):2540-9. 2010.
Miller SJ, Lan Z, Hardiman A, Wu J, Kordich JJ, Patmore D, Hegde R, Cripe TP, Cancelas J, Collins M, Ratner N. Inhibition of Eyes Absent Homolog 4 expression induces malignant peripheral nerve sheath tumor necrosis. Oncogene. 2010.
Miller, SJ, Jessen, WJ, Mehta, T, Hardiman, A, Sites, E, Kaiser, S, Jegga, A, Li, H, Upadhyaya, M, Giovannini, M, Muir, D, Wallace, MR, Lopez, E, Serra, E, Lazaro, C, Stemmer-Rachamimov, A, Page, G, Aronow, BJ, Ratner, N. Integrative genomic analyses of neurofibromatosis tumours identify SOX9 as biomarker and survival gene. EMBO Mol. Medicine, 1(4): 236-248. 2009.
Mahller Y, Williams J, Baird W, Mitton B, Grossheim J, Saeki Y, Cancelas J, Ratner N, Cripe T. Neuroblastoma cell lines contain pluripotent tumor initiating cells that are susceptible to a targeted oncolytic virus. PLoS ONE. 4(1):e4235, 1 – 10. 2009.
Monk KR, Wu J, Williams JP, Meinhardt BA, Fitzgerald ME, Filippi M, Ratner N. Mast cells can contribute to axon-glial dissociation and fibrosis in peripheral nerve. Neuron Glial Biology 3(3):233-44. 2007.Mahller YY, Vaikunth SS, Currier MA, Miller SJ, Ripberger MC, Hsu Y, Mehrian-Shai R, Collins MH, Crombleholme TM, Ratner N, Cripe TP. Oncolytic HSV and erlotinib inhibit tumor growth and angiogenesis in a novel malignant peripheral nerve sheath tumor xenograft model. Molec. Therapy 15(2):279-286. 2007.Nakai Y, Zheng Y, McCollin M, Ratner N. Temporal control of Rac in Schwann cell-axon interaction is disrupted in NF2-mutant schwannoma cells. J. Neurosci. 26(13):3390-5. 2006.Wu J, Crimmins J, Monk K, Williams J, Fitzgerald M, Tedesco S, Ratner N. Perinatal epidermal growth factor receptor blockade prevents peripheral nerve disruption in a mouse model reminiscent of benign world health organization grade I neurofibroma. Am. J. Pathol. 168(5), 1686-1696. 2006.
Miller SJ, Rangwala F, Williams J, Kong S, Jegga A, Aronow B, Frahm S, Kluwe L, Mautner V, Upadhyaya M, Muir D, Wallace M, Hagen J, Quelle DE, Watson M, Perry A, Gutmann DH, Ratner N. Large-scale molecular comparison of human Schwann cells to malignant peripheral nerve sheath tumor cell lines and tissues. Cancer Research. 66(5):2584-91. 2006.Mahller YY, Rangwala F, Ratner N, Cripe TP. Malignant peripheral nerve sheath tumors with high and low Ras-GTP are permissive for oncolytic herpes simplex virus mutants. Pediatric Blood and Cancer. 46(7):745-54. 2006.
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"In tests on mice, MEK inhibition significantly shrunk more than 80 percent of plexiform neurofibromas – the nerve tumors caused by NF1. The data were so compelling that researchers reported the study provided “strong rationale” for testing the drug in a clinical trial."
Read the entire article in Research Horizons.
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