Hippo pathway effectors are associated with glioma patient survival, control cell proliferation and sterol metabolism through TEAD3.

in Brain pathology (Zurich, Switzerland) by Konstantin Masliantsev, Amandine Desette, Anne-Alicia Gonzalez, Inès Garrouche, Anaïs Noblanc, Maleaume Soulard, Mathis Triquard, Serge Milin, Michel Wager, Lucie Karayan-Tapon, Pierre-Olivier Guichet

TLDR

  • In this study, the authors investigated the role of TEAD transcription factors in glioblastomas and identified them as robust prognostic markers of patient outcome.
  • Pharmacological inhibition of YAP/TAZ-TEAD interaction and specific inhibition of TEAD3 resulted in different effects on tumor cell growth and metabolism, highlighting potential therapeutic targets.
  • The study contributes to a better understanding of the role of Hippo effectors in glioblastoma pathophysiology and identifies TEAD3-4 as potential therapeutic targets.

Abstract

Glioblastomas represent the most common and lethal primary brain tumors in the world. Despite therapeutic advances during the last two decades, patient prognosis remains very poor. The Hippo signaling pathway effectors YAP/TAZ-TEADs play a crucial role in tumor progression and represent promising therapeutic targets in gliomas. In this study, we identified and investigated the clinical and biological significance of TEAD transcription factors. Through comprehensive analyses of TCGA glioma data and patient samples, we identified TEAD3-4 transcription factors as robust prognostic markers of patient outcome. Using up to five different patient-derived glioblastoma stem cell cultures, we confirmed the preferential expression and activation of TEAD3-4 along with their transcriptional coactivators YAP/TAZ. Pharmacological inhibition of YAP/TAZ-TEAD interaction by Verteporfin significantly decreased tumor cell growth, whereas specific inhibition of TEAD3 did not impact cell proliferation but affected sterol/cholesterol biosynthetic and metabolic processes. This study contributes to a better understanding of the role of Hippo effectors in glioblastoma pathophysiology. These transcription factors, particularly TEAD3, could potentially serve as therapeutic targets, especially considering recent data on cholesterol homeostasis in glioblastomas.

Overview

  • The study investigates the clinical and biological significance of TEAD transcription factors in glioblastomas, identifying TEAD3-4 as robust prognostic markers of patient outcome.
  • The study uses comprehensive analyses of TCGA glioma data and patient samples, as well as patient-derived glioblastoma stem cell cultures, to confirm the preferential expression and activation of TEAD3-4 and their transcriptional coactivators YAP/TAZ.
  • The primary objective of the study is to contribute to a better understanding of the role of Hippo effectors in glioblastoma pathophysiology and identify potential therapeutic targets, particularly TEAD3 and YAP/TAZ.

Comparative Analysis & Findings

  • Pharmacological inhibition of YAP/TAZ-TEAD interaction by Verteporfin significantly decreased tumor cell growth, while specific inhibition of TEAD3 did not impact cell proliferation but affected sterol/cholesterol biosynthetic and metabolic processes.
  • TEAD3-4 transcription factors were identified as robust prognostic markers of patient outcome through comprehensive analyses of TCGA glioma data and patient samples.
  • The study confirmed the preferential expression and activation of TEAD3-4 along with their transcriptional coactivators YAP/TAZ in patient-derived glioblastoma stem cell cultures.

Implications and Future Directions

  • The findings suggest that TEAD3-4, particularly TEAD3, could potentially serve as therapeutic targets in glioblastomas, especially considering recent data on cholesterol homeostasis in glioblastomas.
  • Future studies could explore novel therapeutic approaches targeting YAP/TAZ-TEAD interaction or TEAD3, as well as investigate the role of cholesterol homeostasis in glioblastoma development and progression.
  • The study highlights the need for further research to understand the role of Hippo effectors in glioblastoma pathophysiology and identifies TEAD3-4 as potential therapeutic targets for future investigation.
Read Full Article