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- W4319293669 abstract "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." @default.
- W4319293669 created "2023-02-07" @default.
- W4319293669 creator A5001323842 @default.
- W4319293669 creator A5014511272 @default.
- W4319293669 creator A5041832272 @default.
- W4319293669 creator A5047560082 @default.
- W4319293669 creator A5066808283 @default.
- W4319293669 creator A5067535356 @default.
- W4319293669 creator A5075113867 @default.
- W4319293669 creator A5083476590 @default.
- W4319293669 date "2023-02-01" @default.
- W4319293669 modified "2023-10-12" @default.
- W4319293669 title "YAP/TAZ activation predicts clinical outcomes in mesothelioma and is conserved in in vitro model of driver mutations" @default.
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