Single tumor-initiating cells evade immune clearance by recruiting type II macrophages

Xiaocan Guo; Yang Zhao; Huan Yan; Yingcheng Yang; Shuying Shen; Xiaoming Dai; Xinyan Ji; Fubo Ji; Xing-Guo Gong; Li Li; Xueli Bai; Xin-Hua Feng; Tingbo Liang; Junfang Ji; Lei Chen; Hongyang Wang; Bin Zhao

doi:10.1101/gad.294348.116

Single tumor-initiating cells evade immune clearance by recruiting type II macrophages

Genes Dev. 2017 Feb 1;31(3):247-259. doi: 10.1101/gad.294348.116. Epub 2017 Feb 21.

Authors

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, Bin Zhao¹

Affiliations

¹ Life Sciences Institute, Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang 310058, China.
² International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China.
³ Institute of Biochemistry, College of Life Science, Zhejiang University, Hangzhou, Zhejiang 310058, China.
⁴ Institute of Aging Research, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
⁵ Department 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.

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.

Keywords: Hippo pathway; YAP; immunosurveillance; liver cancer; macrophage; tumor-initiating cell.

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism
Animals
Carcinoma, Hepatocellular / immunology*
Carcinoma, Hepatocellular / metabolism
Carcinoma, Hepatocellular / pathology
Cell Communication / immunology
Cell Cycle Proteins
Cell Transformation, Neoplastic / immunology*
Cell Transformation, Neoplastic / metabolism
Cell Transformation, Neoplastic / pathology
Cells, Cultured
Hepatocyte Growth Factor / physiology
Hepatocytes / immunology*
Hepatocytes / metabolism
Hepatocytes / pathology
Homeodomain Proteins / physiology
Humans
Liver Neoplasms / immunology*
Liver Neoplasms / metabolism
Liver Neoplasms / pathology
Macrophages / cytology
Macrophages / immunology*
Male
Mice
Mice, Inbred ICR
Mice, Knockout
Neoplastic Stem Cells / cytology
Neoplastic Stem Cells / immunology*
Phosphoproteins / genetics
Phosphoproteins / metabolism
Protein Serine-Threonine Kinases / physiology
Proto-Oncogene Proteins / physiology
Serine-Threonine Kinase 3
Tumor Suppressor Protein p53 / physiology
YAP-Signaling Proteins

Substances

Adaptor Proteins, Signal Transducing
Cell Cycle Proteins
Homeodomain Proteins
Phosphoproteins
Proto-Oncogene Proteins
Tumor Suppressor Protein p53
YAP-Signaling Proteins
Yap1 protein, mouse
macrophage stimulating protein
RAG-1 protein
Hepatocyte Growth Factor
Protein Serine-Threonine Kinases
Serine-Threonine Kinase 3
Stk3 protein, mouse