YAP/TAZ activation predicts clinical outcomes in mesothelioma and is conserved in in vitro model of driver mutations

Richard Cunningham, Siyang Jia, Krishna Purohit, Omar Salem, Ning Sze Hui, Yue Lin, Neil O Carragher, Carsten Gram Hansen*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

The Hippo signalling pathway is dysregulated across a wide range of cancer types and, although driver mutations that directly affect the core Hippo components are rare, a handful is found within pleural mesothelioma (PM). PM is a deadly disease of the lining of the lung caused by asbestos exposure. By pooling the largest-scale clinical datasets publicly available, we here interrogate associations between the most prevalent driver mutations within PM and Hippo pathway disruption in patients, while assessing correlations with a variety of clinical markers. This analysis reveals a consistent worse outcome in patients exhibiting transcriptional markers of YAP/TAZ activation, pointing to the potential of leveraging Hippo pathway transcriptional activation status as a metric by which patients may be meaningfully stratified. Preclinical models recapitulating disease are transformative in order to develop new therapeutic strategies. We here establish an isogenic cell-line model of PM, which represents the most frequently mutated genes and which faithfully recapitulates the molecular features of clinical PM. This preclinical model is developed to probe the molecular basis by which the Hippo pathway and key driver mutations affect cancer initiation and progression. Implementing this approach, we reveal the role of NF2 as a mechanosensory component of the Hippo pathway in mesothelial cells. Cellular NF2 loss upon physiological stiffnesses analogous to the tumour niche drive YAP/TAZ-dependent anchorage-independent growth. Consequently, the development and characterisation of this cellular model provide a unique resource to obtain molecular insights into the disease and progress new drug discovery programs together with future stratification of PM patients.

Original languageEnglish
Pages (from-to)e1190
JournalClinical and Translational Medicine
Issue number2
Publication statusPublished - 5 Feb 2023

Keywords / Materials (for Non-textual outputs)

  • Hippo Signaling Pathway
  • Humans
  • Mesothelioma/genetics
  • Mutation/genetics
  • Protein Serine-Threonine Kinases/metabolism
  • Transcription Factors/genetics
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins
  • YAP-Signaling Proteins


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