Background.The Hippo pathway is the most frequently altered signaling in pleural mesothelioma (PM). Epithelioid PM (ePM) is associated with better outcome than non-epithelioid subtypes, but its prognosis can be heterogeneous. Here, we tried to stratify ePM using the expression levels of the Hippo-TEAD network.Methods.Thirty patients with ePM were included in this study. Tumors were stratified using the expression levels of 74 genes belonging to the Hippo-TEAD network and using the non-negative matrix factorization algorithm. Results were validated using ePM cases from the TCGA cohort. Alterations associated with the molecular subgroups were investigated using mutation and copy number alteration data from TCGA.Results.Two groups of ePM (i.e., HP1 and HP2) were identified and validated using TCGA data. HP2 comprises about one-third of tumors. These tumors are frequently high-grade (73% vs. 35%), have higher levels of downstream Hippo effectors (i.e.,YAP1,WWTR1andTEADs), lower levels ofVSIR—which encodes for VISTA—and poorer PFS and OS. HP2 tumors commonly harbor homodeletions in Hippo core suppressors (25% vs. 3%), while no specific gene mutation or copy number alterations of Hippo genes was associated with the two groups.Conclusions.ePM can be stratified in prognostic subtypes based on the expression levels of the Hippo-TEAD network. Higher levels of downstream Hippo effectors are associated with poor response to platinum-pemetrexed doublet and worse OS. The stratification of ePM based on the activation of the YAP/TAZ-TEAD axis is an intriguing approach in the light of the inhibitors of this signaling that are currently under investigation.
背景：Hippo通路是胸膜间皮瘤（PM）中最常发生改变的信号通路。与上皮样PM（ePM）相比，非上皮样亚型的预后较差，但ePM的预后也存在异质性。本研究尝试利用Hippo-TEAD网络的表达水平对ePM进行分层。 方法：本研究纳入了30例ePM患者。通过分析属于Hippo-TEAD网络的74个基因的表达水平，并采用非负矩阵分解算法对肿瘤进行分层。结果在TCGA队列的ePM病例中得到验证。利用TCGA的突变和拷贝数变异数据，研究了与分子亚组相关的改变。 结果：通过TCGA数据鉴定并验证了两组ePM（即HP1和HP2）。HP2约占肿瘤的三分之一。这些肿瘤通常为高级别（73% vs. 35%），下游Hippo效应因子（即YAP1、WWTR1和TEADs）表达水平较高，而编码VISTA的VSIR表达水平较低，且无进展生存期（PFS）和总生存期（OS）较差。HP2肿瘤常见Hippo核心抑制因子的纯合缺失（25% vs. 3%），但两组间未发现特定的基因突变或Hippo基因拷贝数变异。 结论：基于Hippo-TEAD网络的表达水平，ePM可分为不同预后的亚型。下游Hippo效应因子表达水平较高与铂类-培美曲塞双药化疗反应较差及OS较差相关。鉴于目前正在研究针对YAP/TAZ-TEAD轴信号通路的抑制剂，基于该通路激活状态对ePM进行分层是一种值得关注的方法。
Prognostic Stratification of Epithelioid Pleural Mesothelioma Based on the Hippo-TEADs Network
肿瘤(癌症)患者之家