Abstract 3678: Rewiring of amino acid metabolism in neurofibromatosis type 1-related tumors

Abstract

Abstract Neurofibromatosis type 1 (NF1) is a tumor-predisposing genetic disorder caused by heterozygous mutations in the NF1 gene encoding for the tumor suppressor Neurofibromin. Biallelic NF1 inactivation in Schwann cells leads to the onset of neurofibromas, benign neoplasms that can cause severe medical complications and give rise to malignant peripheral nerve sheath tumors (MPNSTs), for which no treatment exists. Neurofibroma cells undergo bioenergetic changes required to sustain their malignant transformation. Our group has shown that inhibition of the mitochondrial chaperone TRAP1, a master metabolic regulator, hampers MPNST cell tumorigenicity. A growing number of evidence indicates that urea cycle (UC) dysregulation can redirect metabolic substrates to specific biosynthetic routes in many tumor cell types. We have found that a complete UC is absent in MPNST cell models, as they lack ornithine transcarbamylase (OTC), a key UC enzyme that converts ornithine into citrulline. In the absence of TRAP1, MPNST cells strongly reduce arginine levels and accumulate ornithine through the activity of the mitochondrial enzymes arginase 2 (ARG2) and ornithine aminotransferase (OAT). These changes can reverberate on glutamine and proline levels ultimately affecting extracellular matrix deposition, motility and ROS homeostasis, as well as on ornithine-dependent polyamine biosynthesis that can regulate cell growth and proliferation. Surprisingly, in the absence of TRAP1 MPNST cells also accumulate citrulline, even though they do not express either OTC or any nitric oxide synthase (NOS) isoform that converts arginine into citrulline. We ascribe citrulline production to the activity of dimethylarginine dimethylaminohydrolase (DDAH) enzymes, involved in the catabolism of asymmetric dimethylarginines. Induction of DDAHs indicates an elevated protein catabolism that could contribute to tune MPNST cell tumorigenicity. A thorough comprehension of the amino acid metabolism rewiring in NF1-related tumors may unveil new targetable liabilities of cancer cells to be exploited for the design of new effective therapeutic approaches. Citation Format: Martina La Spina. Rewiring of amino acid metabolism in neurofibromatosis type 1-related tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3678.