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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA074177-15
Application #
8215864
Study Section
Hematopoiesis Study Section (HP)
Program Officer
Mufson, R Allan
Project Start
1997-04-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
15
Fiscal Year
2012
Total Cost
$312,768
Indirect Cost
$95,693
Name
Indiana University-Purdue University at Indianapolis
Department
Pediatrics
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Nalepa, Grzegorz; Barnholtz-Sloan, Jill; Enzor, Rikki et al. (2013) The tumor suppressor CDKN3 controls mitosis. J Cell Biol 201:997-1012
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
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; Yang, Feng-Chun; Clapp, D Wade (2012) Pathogenesis of plexiform neurofibroma: tumor-stromal/hematopoietic interactions in tumor progression. Annu Rev Pathol 7:469-95
Zhang, Wei; Rhodes, Steven D; Zhao, Liming et al. (2011) Primary osteopathy of vertebrae in a neurofibromatosis type 1 murine model. Bone 48:1378-87
Chen, Mia; Burgin, Sarah; Staser, Karl et al. (2011) Kinase suppressor of Ras (KSR1) modulates multiple kit-ligand-dependent mast cell functions. Exp Hematol 39:969-76
Staser, Karl; Yang, Feng-Chun; Clapp, David W (2010) Plexiform neurofibroma genesis: questions of Nf1 gene dose and hyperactive mast cells. Curr Opin Hematol 17:287-93
Staser, Karl; Yang, Feng-Chun; Clapp, D Wade (2010) Mast cells and the neurofibroma microenvironment. Blood 116:157-64
Allen, Jayme D; Jaffer, Zahara M; Park, Su-Jung et al. (2009) p21-activated kinase regulates mast cell degranulation via effects on calcium mobilization and cytoskeletal dynamics. Blood 113:2695-705
Yang, Feng-Chun; Ingram, David A; Chen, Shi et al. (2008) Nf1-dependent tumors require a microenvironment containing Nf1+/-- and c-kit-dependent bone marrow. Cell 135:437-48

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