title: Single tumor-initiating cells evade immune clearance by recruiting type II macrophages.
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.
authors.affiliation: Life Sciences Institute, Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Xiaocan
authors.initials: X
authors.lastname: Guo
authors.affiliation: Life Sciences Institute, Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Life Sciences Institute, Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Yan
authors.affiliation: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China.
authors.forename: Yingcheng
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Institute of Biochemistry, College of Life Science, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Shuying
authors.initials: S
authors.lastname: Shen
authors.affiliation: Life Sciences Institute, Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Dai
authors.affiliation: Life Sciences Institute, Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Xinyan
authors.initials: X
authors.lastname: Ji
authors.affiliation: Life Sciences Institute, Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Fubo
authors.initials: F
authors.lastname: Ji
authors.affiliation: Institute of Biochemistry, College of Life Science, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Xing-Guo
authors.initials: XG
authors.lastname: Gong
authors.affiliation: Institute of Aging Research, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Xueli
authors.initials: X
authors.lastname: Bai
authors.affiliation: Life Sciences Institute, Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Feng
authors.affiliation: 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.
authors.forename: Tingbo
authors.initials: T
authors.lastname: Liang
authors.affiliation: Life Sciences Institute, Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Junfang
authors.initials: J
authors.lastname: Ji
authors.affiliation: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.affiliation: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China.
authors.forename: Hongyang
authors.initials: H
authors.lastname: Wang
authors.affiliation: Life Sciences Institute, Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhao
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002450:Cell Communication / Q000276:immunology; D018797:Cell Cycle Proteins; D002471:Cell Transformation, Neoplastic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D017228:Hepatocyte Growth Factor / Q000502:physiology; D022781:Hepatocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018398:Homeodomain Proteins / Q000502:physiology; D006801:Humans; D008113:Liver Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000276:immunology*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology; D000090742:Serine-Threonine Kinase 3; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D000091102:YAP-Signaling Proteins; D000099317:Hippo Kinases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D017228:Hepatocyte Growth Factor; D018398:Homeodomain Proteins; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000090742:Serine-Threonine Kinase 3; D016159:Tumor Suppressor Protein p53; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; C082332:macrophage stimulating protein; C064658:RAG-1 protein; C490818:Stk3 protein, mouse; D000099317:Hippo Kinases
keywords: Hippo pathway; YAP; immunosurveillance; liver cancer; macrophage; tumor-initiating cell