Abstract
Macrophages have been suggested to contribute to constructing a cancer stem cell (CSC) niche. However, whether and how macrophages regulate the activity of CSCs through juxtacrine signaling are poorly understood. Here we report LSECtin, a transmembrane protein highly expressed on tumor-associated macrophages (TAMs), enhances stemness of breast cancer cells (BCCs). We identified BTN3A3, a B7 family member with previously unknown functions as the receptor for LSECtin on BCCs responsible for stemness-promoting effect of LSECtin. In mice bearing human tumor xenografts, either macrophage-specific ablation of LSECtin or silencing of BTN3A3 in BCCs decreased CSC frequency and tumor growth. Admixture of LSECtin-positive macrophages increased the tumorigenic activity of BCCs dependent on BTN3A3. Disruption of the LSECtin-BTN3A3 axis with BTN3A3-Fc or anti-BTN3A3 mAb has a therapeutic effect on breast cancer. These findings define a juxtacrine signaling mechanism by which TAMs promote cancer stemness. Targeting this axis in the CSC niche may provide potential therapies to breast cancer.
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Acknowledgements
We thank Imaging Facility of National Center for Protein Sciences· Beijing (NCPSB) (Mrs. Ping Wu) for Microscopy Imaging, Animal Facility of NCPSB (Mr. Chen Qiu), Flow Cytometry Facility of NCPSB (Mr. Yunxiang Sun and Ms. Mingxin Zhao) for FACS. We thank Mr. Pumin Zhang and Mrs. Jin Peng for cell culturing, Mr. Lichun Tang for gene editing (National Center for Protein Sciences·Beijing), Mr Feng Xu for WB (National Center for Protein Sciences·Beijing). This work was supported by the National Natural Science Foundation (31570901), Beijing Science and Technology Program Foundation (Z141100000214015), National Key R&D Program of China (2018YFA0507500), State Key Laboratory of Proteomics Foundation (SKLP-K201504, SKLP-K201701) and National Basic Research Program of China (973 Program) (2014CBA02000). Project was also funded by China Postdoctoral Science Foundation (2018M633740).
Author contributions
LT and FH planned the project. DL, QL, XW, JW, NL, ZJ, XH, JL, JL and DZ carried out experimental work. PC, GP, and YT analyzed data. DL and LT wrote the paper. All authors discussed the results and commented on the paper.
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Liu, D., Lu, Q., Wang, X. et al. LSECtin on tumor-associated macrophages enhances breast cancer stemness via interaction with its receptor BTN3A3. Cell Res 29, 365–378 (2019). https://doi.org/10.1038/s41422-019-0155-6
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DOI: https://doi.org/10.1038/s41422-019-0155-6
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