PXD063342

PXD063342 is an original dataset announced via ProteomeXchange.

Title	De Novo Pyrimidine Synthesis Is a Collateral Metabolic Vulnerability in NF2-deficient Mesothelioma
Description	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.
HostingRepository	PRIDE
AnnounceDate	2025-07-08
AnnouncementXML	Submission_2025-07-07_18:25:22.882.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Tong Hu
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2025-04-25 08:34:45	ID requested
⏵ 1	2025-07-07 18:25:23	announced

Dataset with its publication pending

submitter keyword: metabolic diversity, de novo pyrimidine synthesis, neurofibromin 2 (NF2),Pleural mesothelioma (PM), synthetic lethality

Duo Xu
contact affiliation	Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
contact email	xuduo@jsph.org.cn
lab head
Tong Hu
contact affiliation	Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
contact email	hutong2017@outlook.com
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/07/PXD063342

PRIDE project URI

• PRIDE
  1. PXD063342
     1. Label: PRIDE project
     2. Name: De Novo Pyrimidine Synthesis Is a Collateral Metabolic Vulnerability in NF2-deficient Mesothelioma