Journal
CELL RESEARCH
Volume 29, Issue 5, Pages 365-378Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41422-019-0155-6
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Funding
- 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]
- National Basic Research Program of China (973 Program) [2014CBA02000]
- China Postdoctoral Science Foundation [2018M633740]
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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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