Peritumoral activation of the Hippo pathway effectors YAP and TAZ suppresses liver cancer in mice

Abstract

The Hippo signaling pathway and its two downstream effectors, the YAP and TAZ transcriptional coactivators, are drivers of tumor growth in experimental models. Studying mouse models, we show that YAP and TAZ can also exert a tumor-suppressive function. We found that normal hepatocytes surrounding liver tumors displayed activation of YAP and TAZ and that deletion of Yap and Taz in these peritumoral hepatocytes accelerated tumor growth. Conversely, experimental hyperactivation of YAP in peritumoral hepatocytes triggered regression of primary liver tumors and melanoma-derived liver metastases. Furthermore, whereas tumor cells growing in wild-type livers required YAP and TAZ for their survival, those surrounded by Yap- and Taz-deficient hepatocytes were not dependent on YAP and TAZ. Tumor cell survival thus depends on the relative activity of YAP and TAZ in tumor cells and their surrounding tissue, suggesting that YAP and TAZ act through a mechanism of cell competition to eliminate tumor cells.

Lineage tracing: technology tool for exploring the development, regeneration, and disease of the digestive system

“…In a previous study, Ivan et al discovered a strange phenomenon: lack of YAP and TAZ in normal hepatocytes surrounding the tumor accelerated tumor growth. Conversely, overexpression of YAP in cells surrounding the tumor contributed to regression of liver cancer [84]; therefore, the survival of liver cancer cells is dependent not on internal YAP/TAZ expression but on YAP/TAZ expression in adjacent liver cells. The above studies used lineage tracing technology to analyze and summarize the two mechanisms of cellular autonomic nerve suppression and non-cellular autonomic tumor suppression and identified additional targets for clinical treatment.…”

Protein phase separation and its role in tumorigenesis

“…However, YAP and TAZ not only promote to tumorigenesis but also have tumor-suppressive functions. For example, activation of YAP in tumor-surrounding cells can suppress liver cancer in mice ( Moya et al, 2019 ).…”

A new perspective on the interaction between the Vg/VGLL1-3 proteins and the TEAD transcription factors

“…The Hippo pathway, which controls organ size and tissue regeneration via the regulation of cell division and apoptosis 1,2 , is an intense field of research in regenerative medicine [3][4][5][6] . Furthermore, deregulation of Hippo signalling in several cancers suggests that molecules targeting this pathway may have antineoplastic properties [7][8][9][10][11] (but see 12,13 ). The Hippo pathway regulates, via a signalling cascade involving the MST1/2 and LATS1/2 protein kinases, the TEAD (TEA/ATTS domain) transcription factors that, upon binding to YAP (Yes associated protein) or VGLL1-3 (Vestigial-like), become transcriptionally active 1, [14][15][16] .…”