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

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

doi:10.1126/science.aaw9886

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

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

Authors

Iván M Moya^#^{1

2}, Stéphanie A Castaldo^#¹, Laura Van den Mooter^#¹, Soheil Soheily^#¹, Leticia Sansores-Garcia¹, Jelle Jacobs³, Inge Mannaerts⁴, Jun Xie¹, Elisabeth Verboven¹, Hanne Hillen¹, Ana Algueró-Nadal¹, Ruchan Karaman¹, Matthias Van Haele⁵, Weronika Kowalczyk¹, Maxime De Waegeneer³, Stefaan Verhulst⁴, Panagiotis Karras⁶, Leen van Huffel¹, Lars Zender^{7

8

9}, Jean-Christophe Marine⁶, Tania Roskams⁵, Randy Johnson¹⁰, Stein Aerts³, Leo A van Grunsven⁴, Georg Halder¹¹

Affiliations

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. [email protected].

^# Contributed equally.

PMID: 31754005
DOI: 10.1126/science.aaw9886

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism*
Animals
Carcinoma, Hepatocellular / metabolism
Carcinoma, Hepatocellular / pathology
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism*
Cell Line, Tumor
Cell Survival
Cholangiocarcinoma / metabolism*
Cholangiocarcinoma / pathology
Hepatocytes / metabolism*
Hippo Signaling Pathway
Humans
Liver Neoplasms / metabolism
Liver Neoplasms / pathology
Liver Neoplasms / secondary
Liver Neoplasms, Experimental / metabolism*
Liver Neoplasms, Experimental / pathology
Melanoma / metabolism
Melanoma / secondary
Mice, Inbred C57BL
Protein Serine-Threonine Kinases / metabolism
Signal Transduction
Trans-Activators / economics
Trans-Activators / genetics
Trans-Activators / metabolism*
Transcription Factors / genetics
Transcription Factors / metabolism
Transcriptional Coactivator with PDZ-Binding Motif Proteins
Tumor Burden
YAP-Signaling Proteins

Substances

Adaptor Proteins, Signal Transducing
Cell Cycle Proteins
Trans-Activators
Transcription Factors
Transcriptional Coactivator with PDZ-Binding Motif Proteins
WWTR1 protein, human
Wwtr1 protein, mouse
YAP-Signaling Proteins
YY1AP1 protein, human
Yap1 protein, mouse
Protein Serine-Threonine Kinases