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Science. 2019 Nov 22;366(6468):1029-1034. doi: 10.1126/science.aaw9886.

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

Author information

1
VIB Center for Cancer Biology and KU Leuven Department of Oncology, University of Leuven, Leuven, Belgium.
2
Facultad de Ingeniería y Ciencias Aplicadas, Universidad de Las Americas, Quito, Ecuador.
3
VIB Center for Brain and Disease Research and KU Leuven Center for Human Genetics, University of Leuven, Leuven, Belgium.
4
Liver Cell Biology Research Group, Vrije Universiteit Brussel, 1090 Brussels, Belgium.
5
Department of Imaging and Pathology, KU Leuven and University Hospitals Leuven, Leuven, Belgium.
6
Laboratory for Molecular Cancer Biology, VIB Center for Cancer Biology and Department of Oncology, KU Leuven, Leuven, Belgium.
7
Department of Medical Oncology and Pneumology, University Hospital Tuebingen, 72076 Tuebingen, Germany.
8
German Cancer Research Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
9
iFIT Cluster of Excellence EXC 2180 "Image Guided and Functionally Instructed Tumour Therapies," University of Tuebingen, Tuebingen, Germany.
10
Department of Cancer Biology, Program in Cancer Biology, Graduate School for Biological Sciences GSBS, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
11
VIB Center for Cancer Biology and KU Leuven Department of Oncology, University of Leuven, Leuven, Belgium. georg.halder@vib.be.
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Contributed equally

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.

PMID:
31754005
DOI:
10.1126/science.aaw9886

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