Prevalence of the Hippo Effectors YAP1/TAZ in Tumors of Soft Tissue and Bone

Abstract

Tumors of soft tissue and bone represent a heterogeneous group of neoplasias characterized by a wide variety of genetic aberrations. Albeit knowledge on tumorigenesis in mesenchymal tumors is continuously increasing, specific insights on altered signaling pathways as a basis for molecularly targeted therapeutic strategies are still sparse. The aim of this study was to determine the involvement of YAP1/TAZ-mediated signals in tumors of soft tissue and bone. Expression levels of YAP1 and TAZ were analyzed by immunohistochemistry in a large cohort of 486 tumor specimens, comprising angiosarcomas (AS), Ewing sarcomas, leiomyosarcomas, malignant peripheral nerve sheath tumors (MPNST), solitary fibrous tumors, synovial sarcomas (SySa), well-differentiated/dedifferentiated/pleomorphic and myxoid liposarcomas (MLS). Moderate to strong nuclear staining of YAP1 and TAZ was detected in 53% and 33%, respectively. YAP1 nuclear expression was most prevalent in MPNST, SySa and MLS, whereas nuclear TAZ was predominately detected in AS, MLS and MPNST. In a set of sarcoma cell lines, immunoblotting confirmed nuclear localization of YAP1 and TAZ, corresponding to their transcriptionally active pool. Suppression of YAP1/TAZ-TEAD mediated transcriptional activity significantly impaired sarcoma cell viability in vitro and in vivo. Our findings identify nuclear YAP1 and TAZ positivity as a common feature in subsets of sarcomas of soft tissue and bone and provide evidence of YAP1/TAZ-TEAD signaling as a specific liability to be considered as a new target for therapeutic intervention. Nuclear YAP1/TAZ expression may represent a biomarker suited to identify patients that could benefit from YAP1/TAZ-TEAD directed therapeutic approaches within future clinical trials.

Prognostic and therapeutic value of the Hippo pathway, RABL6A, and p53-MDM2 axes in sarcomas

“…We and others have previously shown that verteporfin can inhibit the YAP-TEAD interaction in sarcomas and suppress their growth [ 11 , 13 , 67 – 70 ]. In this study, we attempted to determine whether other biomarkers in the RAB6A/YAP/p53-MDM2 axis can also be therapeutically targeted.…”

“…RABL6A has been targeted indirectly by inhibiting cyclin dependent kinases 4/6 and 2 in MPNST [ 43 ]. We and others have shown that TAZ/YAP can be targeted in sarcomas with verteporfin, which targets the TAZ/YAP-TEAD interaction [ 11 , 13 , 67 – 70 ]. p53 has shown the potential for therapeutic targeting [ 80 ].…”

“…Studies have found that TAZ (encoded by WWTR1 ) and YAP are constitutively activated and located in the nucleus in various carcinomas including breast [ 5 ], colon [ 6 ], liver [ 7 ], lung [ 8 ], pancreas [ 9 ], and thyroid [ 4 , 10 ]. More recently, TAZ/YAP were shown to be activated in multiple histological types of sarcoma [ 11 – 13 ]. In epithelioid hemangioendothelioma (EHE), a vascular sarcoma, a WWTR1 - CAMTA1 gene fusion encodes a constitutively activated form of TAZ (TAZ-CAMTA1 fusion protein) that activates a TAZ-like transcriptional program [ 14 – 16 ].…”

Photodynamic Therapy Using Hippo Pathway Inhibitor Verteporfin: A Potential Dual Mechanistic Approach in Treatment of Soft Tissue Sarcomas

“…This is especially true in STS, where immunohistochemical analysis has shown that YAP and TAZ are commonly activated (50% and 66%, respectively) across different histological types of sarcoma and correlate with increased tumor grade and decreased overall survival [43]. Isfort et al expanded upon this work by observing 486 sarcomas and reported TAZ activation in 33% and YAP activation in 53% [44]. In vitro studies show that targeting the YAP/TEAD complex with verteporfin reduces anchorage independent growth in soft agar [43] treatment with verteporfin in two different in vivo models of hepatomegaly, either induced by YAP overexpression or NF2 inactivation (negative regulator of YAP), showed considerable reduction in liver overgrowth [45].…”

Hippo Signaling Pathway as a Central Mediator of Receptors Tyrosine Kinases (RTKs) in Tumorigenesis

“…The main Hippo components are differentially expressed across cancer types, such as in the cases of MST1/2 in soft tissue sarcomas [38][39][40], LATS1/2 in astrocytoma and breast cancers [41,42], TAZ in breast cancer [43,44], and MOB1 in lung and colon cancers [45,46].…”