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Volume 29, No 5, May 2019

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 29 Issue 5, May 2019: 365-378

ORIGINAL ARTICLES

LSECtin on tumor-associated macrophages enhances breast cancer stemness via interaction with its receptor BTN3A3

Di Liu1 , Qian Lu 1,2 , Xing Wang1 , Jun Wang3 , Ning Lu4 , Zefei Jiang5 , Xiaopeng Hao5 , Jianbin Li 5,6 , Jing Liu1 , Pengbo Cao1 , Guilin Peng1 ,Yuandong Tao1 , Dianyuan Zhao1 , Fuchu He1 and Li Tang 1,2

1 State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences·Beijing, Beijing Institute of Lifeomics, Beijing, China; 2Department of Biochemistry and Molecular Biology, Anhui Medical University, Hefei, Anhui Province, China; 3Department of immunobiology and Yale Cancer Center, Yale School of Medicine, New Haven, CT 06511, USA; 4Department of Orthopedics, PLA General Hospital, Beijing, China; 5Department of Breast Cancer, The Fifth Medical Center of PLA General Hospital,Beijing, China and 6Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, China Correspondence: Fuchu He (hefc@nic.bmi.ac.cn) or Li Tang (tangli731@163.com)These authors contributed equally: Di Liu, Qian Lu

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.


https://doi.org/10.1038/s41422-019-0155-6

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