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

被引：171

作者：

Moya, Ivan M. ^{[1
,2
,3
]}

Castaldo, Stephanie A. ^{[1
,2
]}

Van den Mooter, Laura ^{[1
,2
]}

Soheily, Soheil ^{[1
,2
]}

Sansores-Garcia, Leticia ^{[1
,2
]}

Jacobs, Jelle ^{[4
,5
]}

Mannaerts, Inge ^{[6
]}

Xie, Jun ^{[1
,2
]}

Verboven, Elisabeth ^{[1
,2
]}

Hillen, Hanne ^{[1
,2
]}

Alguero-Nadal, Ana ^{[1
,2
]}

Karaman, Ruchan ^{[1
,2
]}

Van Haele, Matthias ^{[7
,8
]}

Kowalczyk, Weronika ^{[1
,2
]}

De Waegeneer, Maxime ^{[4
,5
]}

Verhulst, Stefaan ^{[6
]}

Karras, Panagiotis ^{[9
,10
]}

van Huffel, Leen ^{[1
,2
]}

Zender, Lars ^{[11
,12
,13
]}

Marine, Jean-Christophe ^{[9
,10
]}

Roskams, Tania ^{[7
,8
]}

Johnson, Randy ^{[14
]}

Aerts, Stein ^{[4
,5
]}

van Grunsven, Leo A. ^{[6
]}

Halder, Georg ^{[1
,2
]}

机构：

[1] Univ Leuven, VIB Ctr Canc Biol, Leuven, Belgium

[2] Univ Leuven, KU Leuven, Dept Oncol, Leuven, Belgium

[3] Univ Las Amer, Fac Ingn & Ciencias Aplicadas, Quito, Ecuador

[4] Univ Leuven, VIB Ctr Brain & Dis Res, Leuven, Belgium

[5] Univ Leuven, KU Leuven, Ctr Human Genet, Leuven, Belgium

[6] Vrije Univ Brussel, Liver Cell Biol Res Grp, B-1090 Brussels, Belgium

[7] Katholieke Univ Leuven, Dept Imaging & Pathol, Leuven, Belgium

[8] Univ Hosp Leuven, Leuven, Belgium

[9] Katholieke Univ Leuven, Lab Mol Canc Biol, VIB Ctr Canc Biol, Leuven, Belgium

[10] Katholieke Univ Leuven, Dept Oncol, Leuven, Belgium

[11] Univ Hosp Tuebingen, Dept Med Oncol & Pneumol, D-72076 Tubingen, Germany

[12] German Canc Res Ctr, German Canc Res Consortium DKTK, D-69120 Heidelberg, Germany

[13] Univ Tubingen, iFIT Cluster Excellence EXC Image Guided & F 2180, Tubingen, Germany

[14] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Program Canc Biol, Grad Sch Biol Sci, Houston, TX 77030 USA

来源：

SCIENCE | 2019年 / 366卷 / 6468期

基金：

欧洲研究理事会;

关键词：

TUMOR-SUPPRESSOR; PROLIFERATION; DROSOPHILA; MELANOMA; GROWTH; SIZE;

D O I：

10.1126/science.aaw9886

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：1029 / 1034

页数：6

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