Single tumor-initiating cells evade immune clearance by recruiting type II macrophages
- Xiaocan Guo1,
- Yang Zhao1,
- Huan Yan1,
- Yingcheng Yang2,
- Shuying Shen3,
- Xiaoming Dai1,
- Xinyan Ji1,
- Fubo Ji1,
- Xing-Guo Gong3,
- Li Li4,
- Xueli Bai5,
- Xin-Hua Feng1,
- Tingbo Liang5,
- Junfang Ji1,
- Lei Chen2,
- Hongyang Wang2 and
- Bin Zhao1
- 1Life Sciences Institute, Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang 310058, China;
- 2International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China;
- 3Institute of Biochemistry, College of Life Science, Zhejiang University, Hangzhou, Zhejiang 310058, China;
- 4Institute of Aging Research, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China;
- 5Department of Hepatobiliary and Pancreatic Surgery, Key Laboratory of Cancer Prevention and Intervention, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China
- Corresponding author: binzhao{at}zju.edu.cn
Abstract
Tumor infiltrated type II (M2) macrophages promote tumorigenesis by suppressing immune clearance, promoting proliferation, and stimulating angiogenesis. Interestingly, macrophages were also found to enrich in small foci of altered hepatocytes containing liver tumor-initiating cells (TICs). However, whether and how TICs specifically recruit macrophages and the function of these macrophages in tumor initiation remain unknown due to technical difficulties. In this study, by generating genetically defined liver TICs, we demonstrate that TICs actively recruit M2 macrophages from as early as the single-cell stage. Elimination of TIC-associated macrophages (TICAMs) abolishes tumorigenesis in a manner dependent on the immune system. Mechanistically, activation of the Hippo pathway effector Yes-associated protein (YAP) underlies macrophage recruitment by TICs. These results demonstrate for the first time that macrophages play a decisive role in the survival of single TICs in vivo and provide a proof of principle for TIC elimination by targeting YAP or M2 macrophages.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.294348.116.
- Received November 27, 2016.
- Accepted January 27, 2017.
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