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

Our plain-English summary of Prognostic Stratification of Epithelioid Pleural Mesothelioma Based on the Hippo-TEADs Network, by A.M. Poma, R. Bruno, I. Petrini, et al (Cancers, 2025).

The study

• Authors: A.M. Poma, R. Bruno, I. Petrini, I. Di Stefano, A. Celi, A. Sbrana, S. Cappelli, A. Chella, F. Melfi, M. Lucchi, G. Alì
• Journal: Cancers
• Published: 2025;17(3)
• Read it: PubMed · Publisher · Free full text

Abstract

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.

In plain English

This retrospective study included 30 patients with epithelioid pleural mesothelioma diagnosed in Pisa, Italy, in 2012 to 2019, all given cisplatin or carboplatin plus pemetrexed. Tumors sampled before treatment were grouped by expression of 74 Hippo-TEAD network genes. Two groups emerged, HP1 (17 patients) and HP2 (11), with two samples excluded; HP2 had higher levels of downstream genes YAP1, WWTR1 and TEADs. Progression-free survival was 18 months (95% CI 10 to 28) in HP1 versus 13 (11 to 16) in HP2, and overall survival 50 months (10 to not reached) versus 17 (8 to not reached). High-grade tumors were 35% of HP1 versus 73% of HP2 (not significant). Asbestos exposure was reported for 8 of 16 HP1 patients with known status and 7 of 11 in HP2 (not significant). In 60 epithelioid cases from a public database (TCGA), the same groups appeared; HP2 had worse overall survival (15.4 months, 95% CI 10.8 to 23.9, versus 24.9, 18.8 to 41.5, in HP1) but no significant difference in progression-free survival. The authors concluded that this stratifies epithelioid mesothelioma into prognostic subtypes.

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: Retrospective study of tumor gene expression, with grouping by a clustering algorithm (non-negative matrix factorization) and validation in a public dataset (TCGA)
• Who was studied: 30 patients with epithelioid pleural mesothelioma diagnosed at the University Hospital of Pisa, Italy, 2012 to 2019, all treated with cisplatin or carboplatin plus pemetrexed. The validation set was epithelioid cases from the TCGA pleural mesothelioma cohort (36 in HP1, 24 in HP2).
• Exposure: The study examined expression of 74 Hippo-TEAD network genes in tumors, not asbestos exposure as such. Asbestos exposure history was recorded as a patient characteristic. It was 8 (50%) in HP1, out of 16 HP1 patients with available information (not available for 1 HP1 patient). It was 7 (64%) of 11 in HP2, with p = 0.76. No fiber types or doses were reported.
• Main results:
  • In the Pisa cohort, the algorithm found two groups, HP1 (n = 17) and HP2 (n = 11). Two samples with poor fit were excluded.
  • Pisa cohort: HP2 had higher onco and ratio scores. HP2 also had a lower suppression score, but that difference was not significant.
  • Pisa cohort: progression-free survival was 18 months (95% CI 10 to 28) in HP1 versus 13 months (95% CI 11 to 16) in HP2.
  • Pisa cohort: overall survival was 50 months (95% CI 10 to not reached) in HP1 versus 17 months (95% CI 8 to not reached) in HP2.
  • Pisa cohort: high-grade tumors were 6 (35%) in HP1 versus 8 (73%) in HP2, p = 0.12, not statistically significant.
  • Pisa cohort: VSIR (the gene that codes for the VISTA protein) levels were higher in HP1, but not significantly.
  • TCGA validation: the same analysis found two groups, HP1 (n = 36) and HP2 (n = 24).
  • TCGA validation: HP2 had worse overall survival than HP1, 15.4 months (95% CI 10.8 to 23.9) versus 24.9 months (95% CI 18.8 to 41.5).
  • TCGA validation: there was no significant difference in progression-free survival between the groups.
  • TCGA data: homodeletions in at least one Hippo core suppressor gene occurred in 6 (25%) HP2 tumors versus 1 (3%) HP1 tumor.
  • TCGA data: the two groups were not associated with specific gene mutations.
• The authors' conclusion: The authors concluded that epithelioid pleural mesothelioma forms two molecular groups based on Hippo-TEAD gene expression. In their view, HP2 tumors have higher levels of downstream Hippo effectors, lower VSIR and poorer outcomes. They suggested that HP2 tumors might be less responsive to standard platinum-pemetrexed chemotherapy.
• Limitations the authors state:
  • The original cohort was small.
  • Immune gene data were not fully consistent between the Pisa cohort and the TCGA validation set.
  • The suppression score results were not consistent between the original and validation cohorts.
  • The surgery rate (about 64%) was higher than usual for pleural mesothelioma. The authors attributed this possibly to the small sample and to the institution's surveillance program for asbestos-exposed people.
  • Type of surgery and number of chemotherapy cycles were not evaluated, and their influence on the results cannot be excluded.

Topics

Medical terms in this study, explained in our Lexicon: Epithelioid, Pleural Mesothelioma, Non-epithelioid, Prognosis, Platinum-Pemetrexed.

Related studies

• Presence of pleomorphic features but not growth patterns improves prognostic stratification of epithelioid malignant pleural mesothelioma by 2-tier nuclear grade — Y.Z. Zhang, C. Brambilla, et al. (2020)
• Direct and selective pharmacological disruption of the YAP-TEAD interface by IAG933 inhibits Hippo-dependent and RAS-MAPK-altered cancers — E.A. Chapeau, L. Sansregret, et al. (2024)
• Covalent disruptor of YAP-TEAD association suppresses defective Hippo signaling — M. Fan, W. Lu, et al. (2022)
• Comparative Assessment and High-Throughput Drug-Combination Profiling of TEAD-Palmitoylation Inhibitors in Hippo Pathway Deficient Mesothelioma — L. Evsen, P.J. Morris, et al. (2023)
• Experimental assessment of computationally nominated small molecules targeting the YAP-TEAD interface in Hippo pathway-altered mesothelioma cell models — G.J. Weiss, J.C. Loftus, et al. (2026)
• Gene Expression Analysis of Biphasic Pleural Mesothelioma: New Potential Diagnostic and Prognostic Markers — R. Bruno, A.M. Poma, et al. (2022)

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