Mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF1), the most common genetic disorder in man with a predisposition to cancer. NF1 encodes a GTPase activating protein (GAP) for p21ras (Ras) called neurofibromin, and studies by us and others have shown that the Ras signaling pathways are hyperactive in cells from NF1 patients. Individuals with NF1 have a wide range of malignant and nonmalignant manifestations, including the debilitating plexiform neurofibromas that collectively affect 15-40% of NF1 patients and are a major source of life long morbidity and mortality. Neurofibromas are complex tumors composed of Schwann cells, endothelial cells, fibroblasts, and high concentrations of degranulating mast cells. Studies in cutaneous, mammary, and pancreatic cancers have emphasized the role of inflammatory cells, including mast cells, in altering the tumor microenvironment and facilitating malignant outgrowth. Our group provided the first genetic, cellular, and biochemical evidence that haploinsufficiency of Nf1 alters Ras activity and cell fates in mast cells1, 2. We recently found that Nf1-/- Schwann cells secrete excessive quantities of kit- ligand to recruit mast cells to the tumor microenvironment. 3. Further, using a genetically engineered murine model that closely recapitulates the development of plexiform neurofibromas in NF1 patients, we have now used bone marrow transplantation to demonstrate as a proof of concept that haploinsufficiency of Nf1 in the hematopoietic component of the tumor microenvironment and particularly mast cells is necessary for tumor progression. In this application, we propose to build on these observations and pursue a molecular target identified in the previous funding period. We have recently shown that p21 activated kinase 1 (Pak 1), a serine/threonine kinase, is hyperactivated in Nf1 mast cells2. We hypothesize that Pak1 functions as a key intracellular signaling pathway node that regulates multiple pathologic mast cell processes. Preliminary data from our lab using a Pak1-/- mouse support this hypothesis. Here, we propose to use a genetic intercross to test the role of Pak1 on pathological Nf1 mast cell functions and the biochemical effectors that mediate these functions in vitro. In addition, utilizing the genetically engineered murine model of plexiform neurofibromas and state-of the art experimental imaging developed by investigators on this application, studies to test the role of Pak1 in promoting hematopoietic cell mediated initiation of plexiform neurofibromas in vivo are proposed. Project Narrative: We have previously identified a role for inflammatory mast cells in the genesis of a common type of congenital tumor called plexiform neurofibromas. Studies in this application propose studies in genetically engineered mice to test the role of a protein called Pak1 that we hypothesize are integral to mast cell function and tumor progression. If the hypothesis is correct, we would predict that developing small molecules that inhibit Pak1 function could be useful as a molecular therapy for treatment of plexiform neurofibromas.
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