Journal Article

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

Castaldo, Stéphanie A., Aerts, Stein, Mannaerts, Inge, Algueró-Nadal, Ana, Soheily, Soheil, Van den Mooter, Laura, Sansores-Garcia, Leticia, Kowalczyk, Weronika, De Waegeneer, Maxime, Xie, Jun, Halder, Georg, van Grunsven, Leo A., Verhulst, Stefaan, Johnson, Randy, Van Haele, Matthias, Jacobs, Jelle, Karaman, Ruchan, van Huffel, Leen, Roskams, Tania, Zender, Lars, Verboven, Elisabeth, Hillen, Hanne, Moya, Iván M., Karras, Panagiotis, Marine, Jean-Christophe

2019

Overview

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.

• Publisher: American Association for the Advancement of Science,The American Association for the Advancement of Science
• Subject: Activation / Adaptor Proteins, Signal Transducing - genetics / Adaptor Proteins, Signal Transducing - metabolism / Animal models / Animals / Carcinoma, Hepatocellular - metabolism / Carcinoma, Hepatocellular - pathology / Cell Cycle Proteins - genetics / Cell Cycle Proteins - metabolism / Cell Line, Tumor / Cell Survival / Cholangiocarcinoma - metabolism / Cholangiocarcinoma - pathology / Clonal deletion / Effectors / Hepatocytes / Hepatocytes - metabolism / Humans / Liver / Liver cancer / Liver Neoplasms - metabolism / Liver Neoplasms - pathology / Liver Neoplasms - secondary / Liver Neoplasms, Experimental - metabolism / Liver Neoplasms, Experimental - pathology / Melanoma / Melanoma - metabolism / Melanoma - secondary / Metastases / Mice, Inbred C57BL / Protein-Serine-Threonine Kinases - metabolism / Signal Transduction / Signaling / Survival / Therapeutic applications / Trans-Activators - economics / Trans-Activators - genetics / Trans-Activators - metabolism / Transcription / Transcription Factors - genetics / Transcription Factors - metabolism / Tumor Burden / Tumor cells / Tumorigenesis / Tumors / Yes-associated protein