Patients with neurofibromatosis type 1 (NF1) develop benign peripheral nerve sheath tumors calledneurotlbromas. Within neurofibromas, biallelic mutations in the NF1 gene are found in tumor Schwann cells,indicating that tumorigenesis requires complete loss of function at NF1 in tumor Schwann cells. Malignantprogression of neurofibromas to malignant peripheral nerve sheath tumors occurs in about 10% of NF1patients. No therapies currently exist for neurofibroma or MPNST. The NF1 protein, neurofibromin, is aGTPase-activating protein (GAP) for Ras proteins, molecular switches that control multiple signalingcascades. Loss of neurofibromin leads to increased levels of Ras-GTP in Schwann cells. We used in vitromodel systems for Schwann cell tumorigenesis in NF1 to clarify signaling pathways underlyingtumorigenesis. Surprisingly, we found that increased migration and cAMP accumulation in Nf1 mutantSchwann cells was not accounted for by Ha-Ras-GTP. Rather, these phenotypes may require the relatedand little studied Ras protein TC21/R-Ras2. TC21 uses downstream effectors differently from other Rasproteins. We propose to critically evaluate the relevance of TC21 to formation of neurofibroma and MPNST.Specifically, in Aims 1 & 2 we will define cellular and molecular effects of TC21 in Nf1 mutant Schwann cells,and human MPNST xenografts.
In Aim 3 we will use mouse models to test whether loss of TC21 delays orblocks neurofibroma or MPNST formation Together these studies are anticipated to identify novelintervention points at which to treat human NF1 disease.
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