Abstract 1433: TC21/R-Ras2 is a critical mediator of the Nf1 oncogenic switch

The TC21/R-Ras2 protein is an oncogenic member of the Ras family. Ras proteins act as binary switches which are ‘active’ when bound to GTP and ‘inactive’ when bound to GDP. GTPase activating proteins (GAPs) accelerate the hydrolysis from Ras-GTP to Ras-GDP. This Ras-related GTPase TC21 has transforming capabilities similar to H, N and K-Ras. Activated alleles of TC21 transform epithelial and fibroblast cell lines and induce tumors in vivo. To explore the role of TC21 in cancer we used a model of Ras activation driven by loss of the NF1 tumor suppressor protein, a GAP for all Ras proteins including TC21. Thus loss of NF1 predicts increased levels of activated TC21/R-Ras2. NF1 loss in Schwann cells of the peripheral nervous system causes benign tumors known as neurofibromas. Neurofibromas can transform to sarcomas known as malignant peripheral nerve sheath tumors (MPNSTs). We found that TC21 loss delayed benign neurofibroma formation in Nf1 fl/fl ;DhhCre mice. Nf1 loss increased mRNA encoding the cytokine transforming growth factor-beta (TGF-β) and rendered Schwann cell progenitors insensitive to TGF-β; these phenotypes could be rescued by the Ras-related protein TC21/R-Ras2 and were mediated through TGF-β receptors. Conversely, growth of Nf1;Trp53 brain tumors and NF1 −/− MPNST sarcomas were accelerated by TC21 loss. MPNST from Nf1;Trp53 mice and NF1 −/− MPNST xenografts had increased levels of mRNA encoding TGF- ≤ ligands, and blocking TGF- ≤ decreased sarcoma size induced by shTC21. In benign and malignant tumors an AKT-dependent pathway regulated TGF- ≤ expression. Indicating relevance to human tumorigenesis, global gene expression analyses demonstrated increases in expression of TGF- ≤ ligands and decreases in TGF- ≤ receptors in human neurofibromas and MPNSTs. Thus, we identify critical roles for TC21 in regulation of TGF- ≤ expression. The results are important because TGF- ≤ acts as a tumor suppressor in numerous types of benign tumors and is also known for its oncogenic role in cellular transformation and tumor progression. While it has been known that Ras proteins are involved in TGF- ≤ mediated tumor suppression and oncogenesis, integration between the pathways is incompletely understood, especially in vivo. The study demonstrates that TC21 can be a major regulator of the duality of TGF- ≤ effects on tumorigenesis in vivo. This work was supported by a grant to NR (NIH P50NS057531-03). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1433. doi:1538-7445.AM2012-1433