De novo pyrimidine synthesis is a collateral metabolic vulnerability in NF2-deficient mesothelioma

  • EMBO Mol Med. 2025 Sep;17(9):2258-2298. doi: 10.1038/s44321-025-00278-4.
Duo Xu  #  1 ,  Yanyun Gao  #  2  3 ,  Shengchen Liu  #  4 ,  Shiyuan Yin  5 ,  Tong Hu  5 ,  Haibin Deng  2  3 ,  Tuo Zhang  2  3 ,  Balazs Hegedüs  6 ,  Thomas M Marti  2  3 ,  Patrick Dorn  2  3 ,  Shun-Qing Liang  7 ,  Ralph A Schmid  2  3 ,  Ren-Wang Peng  8  9 ,  Yongqian Shu  10
Affiliations
  • 1. Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. [email protected].
  • 2. Department of General Thoracic Surgery, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
  • 3. Department for BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
  • 4. Department of Cardiothoracic Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
  • 5. Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
  • 6. Department of Thoracic Surgery, University Medicine Essen - Ruhrlandklinik, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Tüschener Weg 40, 45239, Essen, Germany.
  • 7. Department of Medicine, University of Minnesota Twin Cities, 516 Delaware Street SE, Minneapolis, MN, USA.
  • 8. Department of General Thoracic Surgery, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. [email protected].
  • 9. Department for BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. [email protected].
  • 10. Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. [email protected].
  • # Contributed equally.
PMID: 40707702 DOI: 10.1038/s44321-025-00278-4
Abstract

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.

Keywords
De Novo Pyrimidine Synthesis; Metabolic Diversity; Neurofibromin 2 (NF2); Pleural Mesothelioma (PM); Synthetic Lethality.
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