Neurofibromatosis type 1 is a genetic disease with wide ranging consequences on the afflicted individuals ranging from potential intellectual and cognitive deficits to appearance of idiopathic tumors in the peripheral nervous system collectively called neurofibromas. Over the past 12 years we have developed mouse models of NFl with the objective of recapitulating a variety of the pathologic features seen in patients. This proposal continues and expands upon our experience in generating faithful genocopies of NFl-associated neurofibromas. In preceding work funded by this award, our scientific teams joined forces to test the hypothesis that NFl haploinsufficiency outside the Schwann cell lineage provided critical contribution to plexiform neurofibroma development. This hypothesis emerged from studies with our mouse models and the outcome has revealed the importance of mast cells in contributing to the tumor phenotype and ultimately leading to clinical trials to block mast cell activity in patients. In the present application we propose to extend our mouse modeling capabilities to further understand the etiology of plexiform neurofibromas, to identify the source and etiology of dermal neurofibromas, and to use our MPNST models to seek out therapeutic opportunities.
In Specific Aim 1, we will employ tamoxifen-inducible ere driver lines and alternative approaches to better define the source of the cell of origin for plexiform neurofibromas and to define the temporal window of competence for tumor development.
In Specific Aim 2, we will expand on our recent development of a murine model for dermal neurofibromas and on the discovery that skin-derived precursors (SKPs) are the cell of origin for these tumors. We will use multiple techniques including the use of chick/quail embryo transplantation of neural tubes to examine whether the neural crest is the original source of these tumor-competent cells. We will also develop new valuable tamoxifeninducible transgenic Cre driver lines to probe the neural crest-derived tissues for tumor potential. Finally, in Specific Aim 3, we will screen primary MPNST-derived tumor cells to undertake small chemical and RNAi highthroughput screens. These screens aim to identify small molecule compounds and genes that are required for tumor cell proliferation and growth and that can become targets for therapeutics.
ons): Neurofibromas and MPNSTs are incurable cancers that arise in Neurofibromatosis Type 1. We have created mutafions in the NFl gene in mice that allow us to generate faithful models of many of the disease pathologies. In this application, we use our genetic mouse models to study plexiform and dermal neurofibroma tumors to derive crifical informafion for therapy development. We also propose strategies to discover novel potential therapeufic molecules for the treatment of MPNSTs.
|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|
|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|
|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|
|Takeuchi, Koichi; Gertner, Michael J; Zhou, Jing et al. (2013) Dysregulation of synaptic plasticity precedes appearance of morphological defects in a Pten conditional knockout mouse model of autism. Proc Natl Acad Sci U S A 110:4738-43|
|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|
|Stansfield, Brian K; Bessler, Waylan K; Mali, Raghuveer et al. (2013) Heterozygous inactivation of the Nf1 gene in myeloid cells enhances neointima formation via a rosuvastatin-sensitive cellular pathway. Hum Mol Genet 22:977-88|
|Mo, Wei; Chen, Jian; Patel, Amish et al. (2013) CXCR4/CXCL12 mediate autocrine cell- cycle progression in NF1-associated malignant peripheral nerve sheath tumors. Cell 152:1077-90|
|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|
|Mund, Julie A; Estes, Myka L; Yoder, Mervin C et al. (2012) Flow cytometric identification and functional characterization of immature and mature circulating endothelial cells. Arterioscler Thromb Vasc Biol 32:1045-53|
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