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

Our plain-English summary of De novo pyrimidine synthesis is a collateral metabolic vulnerability in NF2-deficient mesothelioma, by D. Xu, Y. Gao, S. Liu, et al (EMBO Molecular Medicine, 2025).

The study

• Authors: D. Xu, Y. Gao, S. Liu, S. Yin, T. Hu, H. Deng, T. Zhang, B. Hegedüs, T.M. Marti, P. Dorn, S.Q. Liang, R.A. Schmid, R.W. Peng, Y. Shu
• Journal: EMBO Molecular Medicine
• Published: 2025;17(9):2258-2298
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

© 2025. The Author(s).

In plain English

This was a laboratory and computational study of pleural mesothelioma (PM), a tumour the authors describe as etiologically associated with asbestos exposure; the study did not report or analyse individual asbestos exposure. The authors analysed public transcriptomic data (65 normal tissues, 328 tumour samples), genetic data from the TCGA-MESO cohort (87 patients), two surgical tissue microarray cohorts (Nanjing, 17 patients, 2011-2020; Bern, 98 patients, 2003-2017), mesothelioma cell lines, patient-derived cells and mouse xenograft models. Clustering of metabolic pathways gave three subtypes. Cluster 1 (47% of samples) showed upregulated pyrimidine synthesis and carried the most NF2 mutations/deletions. In TCGA, NF2 alteration was linked to poorer overall survival, but the authors state this did not reach statistical significance. In the internal cohort, low NF2 protein was significantly linked to poor prognosis. NF2 knockout raised CAD and DHODH, and labelled-glutamine tracing showed more 15N-labelled UMP. In mice, the DHODH inhibitor Brequinar (30 mg/kg, three times weekly) suppressed growth of NF2-deficient tumours, with minimal effect on NF2 wild-type tumours.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: preclinical laboratory study combining multi-omics analysis of public datasets with cell-line experiments and mouse xenograft models
• Who was studied: 328 PM tumour and 65 normal tissue transcriptomes; TCGA-MESO genetic/clinical data (n=87); tissue microarrays from 17 Nanjing patients (2011-2020) and 98 Bern patients (2003-2017); commercial and patient-derived mesothelioma cell lines; nude, NSG and NCG mice
• Exposure: not an exposure study: the variables studied were NF2 loss of function (CRISPR knockout or inherent mutation) and treatment with the DHODH inhibitor Brequinar, alone or with cisplatin
• Main results:
  • Consensus clustering of 328 tumours gave three metabolic subtypes; Cluster 1 was 47% of samples and was marked by upregulated pyrimidine synthesis
  • NF2 alterations were most frequent in Cluster 1 (TCGA-MESO, n=87)
  • In the TCGA series, PM patients with genetic alterations of NF2 had poorer overall survival
  • The authors state that this survival difference in the TCGA series was not statistically significant
  • In the authors' own PM cohort, low NF2 protein was significantly associated with poor prognosis
  • Isotope tracing showed more 15N-labelled UMP in NF2-knockout cells than in controls, indicating increased pyrimidine nucleotide synthesis
  • In mouse models, DHODH inhibition reduced tumour growth and Ki-67-positive cells in NF2-deficient tumours but had minimal effect on wild-type tumours
  • Patient-derived xenografts with inherent NF2 deficiency responded more to DHODH inhibition than NF2-intact xenografts
• The authors' conclusion: The authors concluded, from their commercial and primary preclinical models, that the de novo pyrimidine biosynthesis pathway is a promising synthetic lethal target in NF2-deficient pleural mesothelioma
• Limitations the authors state:
  • The authors note that immunocompromised xenograft models have inherent limitations, especially for inflammation-driven cancers and immunotherapy responses
  • The authors state that the mechanism behind the synergy of cisplatin and the DHODH inhibitor is not yet fully understood
  • The authors state that other physiological factors, such as circulating uridine or hypoxia, may cause intrinsic resistance and need further exploration

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: De Novo, Mesothelioma, Pleural Mesothelioma, Tumor Suppressor Gene, Carcinogenesis.

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• Therapeutic targeting malignant mesothelioma with a novel 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate via its selective uptake by the proton-coupled folate transporter — C. Cherian, S. Kugel Desmoulin, et al. (2013)
• Combined Inhibition of NEDD8-Activating Enzyme and mTOR Suppresses NF2 Loss-Driven Tumorigenesis — J. Cooper, Q. Xu, et al. (2017)
• Gene therapy for diffuse pleural mesotheliomas in preclinical models by concurrent expression of NF2 and SuperHippo — R. Zhu, X. Liu, et al. (2024)
• MEK1 drives oncogenic signaling and interacts with PARP1 for genomic and metabolic homeostasis in malignant pleural mesothelioma — H. Yang, Y. Gao, et al. (2023)
• Intercellular interaction dictates cancer cell ferroptosis via NF2-YAP signalling — J. Wu, A.M. Minikes, et al. (2019)

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