# Prognostic Stratification of Epithelioid Pleural Mesothelioma Based on the Hippo-TEADs Network

## TL;DR

This study identifies two subtypes of epithelioid pleural mesothelioma based on Hippo-TEAD network activity, with one subtype showing worse survival and specific genetic changes.

## Contribution

A novel prognostic stratification of epithelioid pleural mesothelioma using Hippo-TEAD network expression levels and genetic alterations.

## Key findings

- HP2 tumors, one-third of cases, show higher Hippo effectors and worse survival.
- HP2 tumors often have homodeletion of Hippo suppressors and lower VISTA expression.
- Stratification based on Hippo-TEAD activity may guide treatment in light of emerging inhibitors.

## Abstract

The Hippo pathway is the most commonly altered signaling in pleural mesothelioma (PM). The aim of our retrospective study was to stratify patients with epithelioid PM using the expression levels of the Hippo-TEAD network. We identified two groups of tumors; HP2 tumors, which are about one-third of the total, have higher levels of downstream Hippo oncogenes, lower mRNA levels of the immune checkpoint VISTA, and poorer progression-free and overall survival. These tumors often harbor homodeletion of Hippo core suppressors.

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, WWTR1 and TEADs), lower levels of VSIR—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.