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Studying the Effects of Tumor-Secreted Paracrine Ligands on Macrophage Activation using Co-Culture with Permeable Membrane Supports
Published on: November 28, 2019
Single tumor-initiating cells evade immune clearance by recruiting type II macrophages
Xiaocan Guo1, Yang Zhao1, Huan Yan1
1Life Sciences Institute, Innovation Center for Cell Signaling Network, 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.
Insights
Tumor-initiating cells (TICs) actively recruit M2 macrophages, crucial for early liver tumor development. Eliminating these tumor-associated macrophages (TICAMs) prevents tumor formation, highlighting YAP as a therapeutic target.
Area of Science:
- Hepatology
- Immunology
- Oncology
Background:
- M2 macrophages promote tumor growth by hindering immune clearance, boosting proliferation, and stimulating angiogenesis.
- Macrophages accumulate near liver tumor-initiating cells (TICs), but their recruitment and role in tumor initiation are unclear.
Purpose of the Study:
- To investigate if and how TICs recruit macrophages.
- To determine the function of these macrophages in liver tumor initiation.
Main Methods:
- Generation of genetically defined liver TICs.
- Elimination of TIC-associated macrophages (TICAMs) to assess tumorigenesis.
- Investigating the role of the Hippo pathway effector YAP in macrophage recruitment.
Main Results:
- TICs actively recruit M2 macrophages starting from the single-cell stage.
- Elimination of TICAMs abolished tumorigenesis, dependent on the immune system.
- Activation of YAP in TICs drives M2 macrophage recruitment.
Conclusions:
- Macrophages are essential for the survival of single TICs in vivo.
- Targeting YAP or M2 macrophages offers a therapeutic strategy for TIC elimination and liver cancer prevention.
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