Mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF1). NF1 encodes a GTPase activating protein (GAP) for p21ras (Ras) called neurofibromin. Individuals with NF1 have a wide range of manifestations including the pathognomonic cutaneous neurofibromas and plexiform neurofibromas. Studies in cutaneous, mammary, and pancreatic cancers have emphasized the role of inflammatory cells altering the microenvironment and facilitating malignant outgrowth. Similarly, utilizing genetically engineered mice that are deficient in the murine homologue of NF1 (Nf1), our collaborator, Dr. Parada (Zhu, Science, 2002), found that haploinsufficiency of Nf1 in lineages within the tumor microenvironment was required for development of neurofibromas. Based on these prior insights, a major focus of this application will be to functionally define how the interactions between the known Nf1 +/- cells in the microenvironment promote neurofibroma formation utilizing both human and murine cells. Defining the molecular and biochemical nature of these interactions in promoting tumorigenesis is critical for identifying drug targets to be used in preclinical trials. Our group previously provided the first genetic, cellular, and biochemical evidence that haploinsufficiency of Nf1 alters cell fates in mast cells (Ingram, JEM, 2000, 2001). Mast cells release growth factors and other molecules that collectively promote angiogenesis, the alteration of the extracellular matrix and cell growth. Our original studies focused on the role of haploinsufficiency of Nf1 in modulating mast cell functions and the biochemical mechanisms underlying the recruitment of mast cells to the tumor microenvironment (Yang, JCI 2003). We now propose to extend these observations to examine the mechanisms underlying the role of mast cells in altering Nf1 -I- Schwann cell fates, and other lineages within the neurofibroma microenvironment. We hypothesize that Nf1 +/- endothelial cells and fibroblasts have an intrinsic gain of function phenotypes which are further perturbed by secretory proteins released by Nf1 +/- mast cells. We will test these hypotheses with in vitro and in vivo studies, utilizing genetic intercrosses and pharmacologic agents currently used to treat other cancers and state of the art tissue imaging. Finally, studies will be conducted in primary human lineages of the tumor microenvironment to verify that the murine model faithfully recapitulates the phenotypes in human lineages.
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