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

Our plain-English summary of YAP/TAZ activation predicts clinical outcomes in mesothelioma and is conserved in in vitro model of driver mutations, by R. Cunningham, S. Jia, K. Purohit, et al (Clinical and Translational Medicine, 2023).

The study

• Authors: R. Cunningham, S. Jia, K. Purohit, O. Salem, N.S. Hui, Y. Lin, N.O. Carragher, C.G. Hansen
• Journal: Clinical and Translational Medicine
• Published: 2023;13(2):e1190
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.

In plain English

This laboratory and data-analysis study combined two public pleural mesothelioma (PM) datasets, TCGA (87 patients) and Bueno (211 patients), and built a cell-line model. Patients were grouped both by NF2 and BAP1 mutation status and by markers of YAP/TAZ activity, part of the Hippo signalling pathway. Mutation status alone showed no significant association with subtype, stage or survival. Patients carrying a Hippo kinase module inactivating mutation (NF2, LATS1/2, SAV1) showed higher presumed active YAP protein and higher expression of a 22-gene YAP/TAZ signature. In the pooled data, patients classed as YAP/TAZ signature high had shorter median survival (13.32 months versus 23.52 months; HR = 1.75, n = 296). Higher YAP/TAZ activity was found in late-stage disease and the sarcomatoid subtype. In CRISPR knockout MeT-5A mesothelial cells, NF2 loss abolished YAP/TAZ inactivation on serum starvation. It reduced, but did not remove, YAP responses to crowding and soft substrates. NF2 loss increased anchorage-independent growth, and BAP1 loss decreased it. The authors concluded that Hippo dysregulation is associated with worse PM prognosis.

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: Pooled re-analysis of two publicly available clinical genomic/transcriptomic datasets combined with laboratory experiments using a CRISPR-Cas9 isogenic mesothelial cell-line model
• Who was studied: Pleural mesothelioma patients from two published cohorts (TCGA, 87 patients; Bueno et al., 211 patients; 296 in the pooled survival analysis; 184 in the pooled signature analysis; 63 for the RPPA protein analysis), plus the human mesothelial cell line MeT-5A and its knockout clones
• Exposure: Not an exposure study. The factors examined were tumour driver mutations (NF2, BAP1, LATS1/2, SAV1) and Hippo pathway/YAP-TAZ transcriptional activation; asbestos is named only as the cause of the disease in the introduction
• Main results:
  • Patients were first grouped by NF2 and BAP1 mutation status, and this grouping showed no significant association with transcriptomic subtype, clinical stage or overall survival
  • In the pooled patient data, those classed as YAP/TAZ signature high had shorter median survival than signature low patients: 13.32 months versus 23.52 months
  • Hazard ratio for the YAP/TAZ signature high group in the pooled cohorts
  • Protein data (TCGA cohort, n = 63) showed higher presumed active YAP in patients with a Hippo kinase module inactivating mutation
  • Higher YAP/TAZ activity was seen in later-stage disease and the sarcomatoid subtype
  • In MeT-5A cells, NF2 knockout removed the YAP and TAZ phosphorylation (inactivation) normally seen on serum starvation in wild-type cells
  • With increasing cell contact, NF2 knockout cells were markedly less sensitive than wild-type cells to the drop in nuclear YAP, though some decrease in nuclear YAP still occurred
  • A residual decrease in nuclear YAP with cell contact remained in NF2 knockout cells
  • On soft substrates, wild-type cells showed increased YAP phosphorylation, while NF2 knockout cells showed only a minor increase
  • As cells became confluent, NF2 knockout clones showed higher YAP/TAZ signature expression than wild-type MeT-5A cells
  • NF2 knockout cells grew more without anchorage in soft agar, and this depended mainly on YAP; NF2-TAZ double knockout had only a modest effect
  • Gene expression changes caused by BAP1 knockout in cells correlated with those in BAP1 mutant patients when the comparison was restricted to genes dysregulated in vitro
  • In contrast to NF2 loss, BAP1 knockout in MeT-5A cells reduced anchorage-independent growth
• The authors' conclusion: The authors concluded that Hippo signalling disruption is closely associated with worse prognosis in PM patients and that patients might be stratified by markers of YAP/TAZ activity rather than by driver mutation status. They presented their cell model as a preclinical resource.
• Limitations the authors state:
  • The cell model had not been tested in living animals
  • BAP1 loss in patients was inferred from mutation status alone, which may limit the survival analysis
  • The cultured cells lack an immune component or stroma
  • The mechanism by which BAP1 loss affects the Hippo transcriptional module in mesothelial cells was not established

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelioma, Pleural Mesothelioma, Asbestos Exposure, Mesothelial Cells, Discovery.

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• The Emerging Role of the Hippo Pathway in Lung Cancers: Clinical Implications — S.L. Teoh, S. Das (2017)
• TAZ activation by Hippo pathway dysregulation induces cytokine gene expression and promotes mesothelial cell transformation — A. Matsushita, T. Sato, et al. (2019)
• Intercellular interaction dictates cancer cell ferroptosis via NF2-YAP signalling — J. Wu, A.M. Minikes, et al. (2019)
• Immunohistochemistry for NF2, LATS1/2, and YAP/TAZ Fails to Separate Benign From Malignant Mesothelial Proliferations — B.S. Sheffield, J. Lorette, et al. (2016)
• Hippo pathway gene mutations in malignant mesothelioma: revealed by RNA and targeted exon sequencing — A. Miyanaga, M. Masuda, et al. (2015)

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