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

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.

Deciphering the role of transcription factors in glioblastoma cancer stem cells

“…This interaction extends to modulating the tumor immune response, with emerging evidence highlighting the role of YAP/TAZ in immune evasion. Preclinical models have shown promising results when targeting YAP/TAZ with drugs, such as verteporfin, which disrupt the YAP-TEAD interaction, and their potential to inhibit GBM growth and enhance susceptibility to immune-mediated destruction has been explored [149][150][151][152]. This indicates that YAP/TAZ are key obstacles in GSC differentiation and immune evasion therapy, and future research focusing on exploring the complex interactions of YAP/TAZ with multiple cellular pathways and the immune system, as well as developing more targeted and effective therapeutic strategies, will be of vital importance.…”