Xu Duo, Gao Yanyun, Liu Shengchen, Yin Shiyuan, Hu Tong, Deng Haibin, Zhang Tuo, Hegedüs Balazs, Marti Thomas M, Dorn Patrick, Liang Shun-Qing, Schmid Ralph A, Peng Ren-Wang, Shu Yongqian
Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Department of General Thoracic Surgery, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
EMBO Mol Med. 2025 Jul 24. doi: 10.1038/s44321-025-00278-4.
Pleural mesothelioma (PM) is one of the deadliest cancers, with limited therapeutic options due to its therapeutically intractable genome, which is characterized by the functional inactivation of tumor suppressor genes (TSGs) and high tumor heterogeneity, including diverse metabolic adaptations. However, the molecular mechanisms underlying these metabolic alterations remain poorly understood, particularly how TSG inactivation rewires tumor metabolism to drive tumorigenesis and create metabolic dependencies. Through integrated multi-omics analysis, we identify for the first time that NF2 loss of function defines a distinct PM subtype characterized by enhanced de novo pyrimidine synthesis, which NF2-deficient PM cells are critically dependent on for sustained proliferation in vitro and in vivo. Mechanistically, NF2 loss activates YAP, a downstream proto-oncogenic transcriptional coactivator in the Hippo signalling pathway, which in turn upregulates CAD and DHODH, key enzymes in the de novo pyrimidine biosynthesis pathway. Our findings provide novel insights into metabolic reprogramming in PM, revealing de novo pyrimidine synthesis as a synthetic lethal vulnerability in NF2-deficient tumors. This work highlights a potential therapeutic strategy for targeting NF2-deficient mesothelioma through metabolic intervention.
胸膜间皮瘤（PM）是最致命的癌症之一，由于其具有治疗棘手的基因组，治疗选择有限，其特点是肿瘤抑制基因（TSG）功能失活以及肿瘤异质性高，包括多种代谢适应性改变。然而，这些代谢改变背后的分子机制仍知之甚少，特别是TSG失活如何重塑肿瘤代谢以驱动肿瘤发生并产生代谢依赖性。通过综合多组学分析，我们首次发现NF2功能丧失定义了一种独特的PM亚型，其特征是从头嘧啶合成增强，NF2缺陷的PM细胞在体外和体内的持续增殖严重依赖于此。从机制上讲，NF2缺失激活YAP，YAP是Hippo信号通路中的一种下游原癌基因转录共激活因子，进而上调CAD和DHODH，这两种是从头嘧啶生物合成途径中的关键酶。我们的研究结果为PM中的代谢重编程提供了新的见解，揭示了从头嘧啶合成是NF2缺陷肿瘤中的一种合成致死性弱点。这项工作突出了通过代谢干预靶向NF2缺陷型间皮瘤的潜在治疗策略。
