Ras proteins are molecular switches that in their GTP-bound state control intracellular signaling cascades. Ras signaling is inactivated by GTPase-activating proteins (GAPs), including the tumor suppressor NF1. NF1 loss of function mutations have recently been implicated in driving neuroblastoma, brain, lung, thyroid and other tumor types and implicated in resistance to therapy. In addition, inherited NF1 mutations result in Neurofibromatosis type 1, a disease in which patients develop incurable benign peripheral nerve sheath Schwann cell tumors called neurofibromas. NF1 patients are also predisposed to aggressive sarcomas, MPNST, which are a leading cause of death in NF1 patients. The goals of this application are two-fold. We shall use NF1 loss of function to delineate Ras-specific pathways in neurofibroma cells. This is because NF1 is a GAP for all Ras proteins: H-, N-, K-, M-, R-Ras and RRas2/TC21, and may have additional, non-Ras, functions. When there is complete loss of NF1, all Ras proteins are activated, so that NF1 models provide a unique opportunity to study the contributions of individual Ras proteins to tumorigenesis in vivo.
In Aim 1 we will test whether loss of H-Ras specifically delays or blocks neurofibroma formation in mouse models driven by NF1 loss of function, alone or in combination with RRas2 loss. We will also determine if H-Ras activation is sufficient to promote neurofibroma formation.
In Aim 2 we will test if Ras activation is sufficient for neurofibroma formation, using a new Nf1 mutant allele and use specialized Schwann cell systems to define Ras-specific effects in NF1 mutant cells.
In Aim 3 we will validate our state-of-the-art exome sequencing to identify Ras-related signaling pathway mutations in Schwann cells that co-operate with NF1 loss of function to promote NF1 tumorigenesis. Together these studies will define Ras isoform specific functions in cancer cells, and clarify molecular signals that drive neurofibroma formation.
Remarkable progress has been made in identification of somatic NF1 gene mutations in common tumor types (brain, lung, neuroblastoma, pheochromocytoma). Germline NF1 gene mutations predispose affected individuals to nerve and brain tumors. The NF1 protein is a direct regulator of six Ras proteins. A primary goal of this project is to identify critical Ras proteins which mediate nerve tumorigenesis. A second goal of this project is to determine the array of mutations that co-operate with Ras in neurofibroma tumorigenesis. The overarching aim of the project is to identify unique intervention points for novel NF1 therapies.
| Coover, Robert A; Healy, Tabitha E; Guo, Li et al. (2018) Tonic ATP-mediated growth suppression in peripheral nerve glia requires arrestin-PP2 and is evaded in NF1. Acta Neuropathol Commun 6:127 |
| Choi, Kwangmin; Komurov, Kakajan; Fletcher, Jonathan S et al. (2017) An inflammatory gene signature distinguishes neurofibroma Schwann cells and macrophages from cells in the normal peripheral nervous system. Sci Rep 7:43315 |
