The Hippo Pathway Effectors YAP/TAZ-TEAD Oncoproteins as Emerging Therapeutic Targets in the Tumor Microenvironment

Reza Bayat Mokhtari; Neda Ashayeri; Leili Baghaie; Manpreet Sambi; Kosar Satari; Narges Baluch; Dmitriy A Bosykh; Myron R Szewczuk; Sayan Chakraborty

doi:10.3390/cancers15133468

The Hippo Pathway Effectors YAP/TAZ-TEAD Oncoproteins as Emerging Therapeutic Targets in the Tumor Microenvironment

Cancers (Basel). 2023 Jul 2;15(13):3468. doi: 10.3390/cancers15133468.

Authors

Reza Bayat Mokhtari^{1

2}, Neda Ashayeri³, Leili Baghaie², Manpreet Sambi², Kosar Satari³, Narges Baluch⁴, Dmitriy A Bosykh¹, Myron R Szewczuk², Sayan Chakraborty¹

Affiliations

¹ Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
² Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada.
³ Division of Hematology and Oncology, Department of Pediatrics, Ali-Asghar Children Hospital, Iran University of Medical Science, Tehran 1449614535, Iran.
⁴ Department of Immunology and Allergy, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.

Abstract

Various cancer cell-associated intrinsic and extrinsic inputs act on YAP/TAZ proteins to mediate the hyperactivation of the TEAD transcription factor-based transcriptome. This YAP/TAZ-TEAD activity can override the growth-limiting Hippo tumor-suppressor pathway that maintains normal tissue homeostasis. Herein, we provide an integrated summary of the contrasting roles of YAP/TAZ during normal tissue homeostasis versus tumor initiation and progression. In addition to upstream factors that regulate YAP/TAZ in the TME, critical insights on the emerging functions of YAP/TAZ in immune suppression and abnormal vasculature development during tumorigenesis are illustrated. Lastly, we discuss the current methods that intervene with the YAP/TAZ-TEAD oncogenic signaling pathway and the emerging applications of combination therapies, gut microbiota, and epigenetic plasticity that could potentiate the efficacy of chemo/immunotherapy as improved cancer therapeutic strategies.

Keywords: Hippo signaling pathway; TEAD; YAP/TAZ; cancer; carcinogenesis; combination therapies; drug resistance; gut microbiota; immunotherapy; tumor microenvironment.

Publication types

Review

Grants and funding

R.B.M. is the recipient of the 2022 Mitacs Accelerate Fellowship Award. L.B. is the recipient of the 2022 Queen’s Graduate Award (QGA). All authors have read and agreed to the published version of the manuscript. This work was supported by grants to S.C. from the CCSG grant of the Developmental Therapeutics Program at Roswell Park Cancer Institute and the Department of Pharmacology and Therapeutics core funds.