Plexiform neurofibromas are complex tumors characterized by tumorigenic Schwann cells, inflammatory cells, neoangiogenesis and alterations of the extracellular matrix. Our previous work provided genetic, cellular, and biochemical evidence that haploinsufficiency of Nfl alters Ras activity and cell fates in mast cells and that ckit activation of the hematopoietic system is required in the initiation of plexiform tumor formation in a murine model. In this application, we propose to build oh these observations to identify the underpinning mechanisms of how c-kit mediates its biological effects, and to identify experimental processes that would complement ckit mediated experimental therapeutics in the clinic. Three basic processes will be examined. First, kit activation is known to cooperate with integrin signals in enabling myeloid cells to adhere to blood vessel walls and emigrate from the blood to the emerging tumor. We have recently established that Nf 1 +/- mast cells preferentially adhere to alpha4beta1, an integrin that has a key role in mast cell adhesion to endothelium and in local sites of inflammation. We hypothesize that alpha4beta1 is crucial in the recruitment of Nf1+/- mast cells to the tumor microenvironment in promoting local mast cell proliferation and survival, and in the secretion of molecules that promote neoangiogenesis. We propose studies to test this hypothesis in vitro and in vivo. Second, MMPs are secreted molecules that promote the release of preformed growth factors to the circulation and degrade the extracellular matrix of tissues allowing invasion of inflammatory and stromal cells leading to tumor progression. In preliminary studies we detect one specific MMP that is preferentially expressed and activated. Studies to specifically test the role of this protease are proposed. Finally, the specific downstream paracrine signals that lead to alterations of the extracellular matrix and neoangiogenesis are incompletely understood. Tumor-associated macrophages are known to enhance neoangiogenesis and facilitate malignant outgrowth. We recently established that large populations of angiogenic macrophages are found in peripheral blood and in the neurofibromas of Krox20;Nfl flox/- mice. We hypothesize that macrophage recruitment and their role in neoangiogenesis is a key downstream event following mast cell recruitment to the tumor and, therefore, processes that inhibit this activity will prevent or delay tumor progression. Adoptive transfer experiments are proposed to test this hypothesis.

Public Health Relevance

This is an application that focuses on the use of a genetically engineered murine model to identify key molecular processes in plexiform neurofibroma progression. Studies utilize genetic intercrosses and adoptive transfer experiments to test the proposed hypotheses.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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University of Texas Sw Medical Center Dallas
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Bessler, Waylan K; Hudson, Farlyn Z; Zhang, Hanfang et al. (2016) Neurofibromin is a novel regulator of Ras-induced reactive oxygen species production in mice and humans. Free Radic Biol Med 97:212-222
Bessler, Waylan K; Kim, Grace; Hudson, Farlyn Z et al. (2016) Nf1+/- monocytes/macrophages induce neointima formation via CCR2 activation. Hum Mol Genet 25:1129-39
Ferguson, Michael J; Rhodes, Steven D; Jiang, Li et al. (2016) Preclinical Evidence for the Use of Sunitinib Malate in the Treatment of Plexiform Neurofibromas. Pediatr Blood Cancer 63:206-13
Stansfield, Brian K; Ingram, David A (2015) Clinical significance of monocyte heterogeneity. Clin Transl Med 4:5
Sanchez-Ortiz, Efrain; Cho, Woosung; Nazarenko, Inga et al. (2014) NF1 regulation of RAS/ERK signaling is required for appropriate granule neuron progenitor expansion and migration in cerebellar development. Genes Dev 28:2407-20
Chau, Vincent; Lim, S Kyun; Mo, Wei et al. (2014) Preclinical therapeutic efficacy of a novel pharmacologic inducer of apoptosis in malignant peripheral nerve sheath tumors. Cancer Res 74:586-97
Li, Fang; Downing, Brandon D; Smiley, Lucy C et al. (2014) Neurofibromin-deficient myeloid cells are critical mediators of aneurysm formation in vivo. Circulation 129:1213-24
Stansfield, Brian K; Bessler, Waylan K; Mali, Raghuveer et al. (2014) Ras-Mek-Erk signaling regulates Nf1 heterozygous neointima formation. Am J Pathol 184:79-85
Staser, Karl; Park, Su-Jung; Rhodes, Steven D et al. (2013) Normal hematopoiesis and neurofibromin-deficient myeloproliferative disease require Erk. J Clin Invest 123:329-34
Staser, Karl; Shew, Matthew A; Michels, Elizabeth G et al. (2013) A Pak1-PP2A-ERM signaling axis mediates F-actin rearrangement and degranulation in mast cells. Exp Hematol 41:56-66.e2

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