TY - JOUR
T1 - Peritumoral activation of the Hippo pathway effectors YAP and TAZ suppresses liver cancer in mice
AU - Moya, Iván M.
AU - Castaldo, Stéphanie A.
AU - van den Mooter, Laura
AU - Soheily, Soheil
AU - Sansores-Garcia, Leticia
AU - Jacobs, Jelle
AU - Mannaerts, Inge
AU - Xie, Jun
AU - Verboven, Elisabeth
AU - Hillen, Hanne
AU - Algueró-Nadal, Ana
AU - Karaman, Ruchan
AU - van Haele, Matthias
AU - Kowalczyk, Weronika
AU - de Waegeneer, Maxime
AU - Verhulst, Stefaan
AU - Karras, Panagiotis
AU - van Huffel, Leen
AU - Zender, Lars
AU - Marine, Jean Christophe
AU - Roskams, Tania
AU - Johnson, Randy
AU - Aerts, Stein
AU - van Grunsven, Leo A.
AU - Halder, Georg
N1 - Funding Information:
We thank X. Chen, P. Hackett, C. Der, C. Distelhorst, and E. Kowarz for depositing plasmids at Addgene and D. Pan for the Apo>hYAP1SA mouse strain. S.A.C., L.V.d.M., and E.V. were supported by doctoral fellowships from the Research Foundation Flanders (FWO). I.M. was supported by a postdoctoral fellowship from FWO. L.Z. was supported by the German Research Foundation: DFG EXC 2180 – 390900677 [Image Guided and Functionally Instructed Tumour Therapies (iFIT)], FOR2314, SFB-TR209, Gottfried Wilhelm Leibniz Program, the German Ministry for Education and Research (BMBF): eMed/Multiscale HCC, the European Research Council: Consolidator grant “CholangioConcept,” and the German Center for Translational Cancer Research (DKTK). L.A.v.G. and G.H. were supported by grants from FWO, and G.H. by a grant from Stichting tegen Kanker (FAF-F/2016/867).
Publisher Copyright:
Copyright © 2019 The Authors,
PY - 2019/11/22
Y1 - 2019/11/22
N2 - 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.
AB - 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.
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U2 - 10.1126/science.aaw9886
DO - 10.1126/science.aaw9886
M3 - Article
C2 - 31754005
AN - SCOPUS:85075461086
SN - 0036-8075
VL - 366
SP - 1029
EP - 1034
JO - Science
JF - Science
IS - 6468
ER -