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

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 vi

SUBMITTER: Xu D 

PROVIDER: S-EPMC12423300 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature