ATP11B inhibits breast cancer metastasis in a mouse model by suppressing externalization of nonapoptotic phosphatidylserine
Jun Xu, Sek Man Su, Xin Zhang, Un In Chan, Ragini Adhav, Xiaodong Shu, Jianlin Liu, Jianjie Li, Lihua Mo, Yuqing Wang, Tingting An, Josh Haipeng Lei, Kai Miao, Chu-Xia Deng, Xiaoling Xu
Jun Xu, Sek Man Su, Xin Zhang, Un In Chan, Ragini Adhav, Xiaodong Shu, Jianlin Liu, Jianjie Li, Lihua Mo, Yuqing Wang, Tingting An, Josh Haipeng Lei, Kai Miao, Chu-Xia Deng, Xiaoling Xu
View: Text | PDF
Research Article Oncology

ATP11B inhibits breast cancer metastasis in a mouse model by suppressing externalization of nonapoptotic phosphatidylserine

Abstract

Cancer metastasis is the cause of the majority of cancer-related deaths. In this study, we demonstrated that no expression or low expression of ATP11B in conjunction with high expression of PTDSS2, which was negatively regulated by BRCA1, markedly accelerates tumor metastasis. Further analysis revealed that cells with low ATP11B expression and high PTDSS2 expression (ATP11BloPTDSS2hi cells) were associated with poor prognosis and enhanced metastasis in breast cancer patients in general. Mechanistically, an ATP11BloPTDSS2hi phenotype was associated with increased levels of nonapoptotic phosphatidylserine (PS) on the outer leaflet of the cell membrane. This PS increase serves as a global immunosuppressive signal to promote breast cancer metastasis through an enriched tumor microenvironment with the accumulation of myeloid-derived suppressor cells and reduced activity of cytotoxic T cells. The metastatic processes associated with ATP11BloPTDSS2hi cancer cells can be effectively overcome by changing the expression phenotype to ATP11BhiPTDSS2lo through a combination of anti-PS antibody with either paclitaxel or docetaxel. Thus, blocking the ATP11BloPTDSS2hi axis provides a new selective therapeutic strategy to prevent metastasis in breast cancer patients.

Authors

Jun Xu, Sek Man Su, Xin Zhang, Un In Chan, Ragini Adhav, Xiaodong Shu, Jianlin Liu, Jianjie Li, Lihua Mo, Yuqing Wang, Tingting An, Josh Haipeng Lei, Kai Miao, Chu-Xia Deng, Xiaoling Xu

×

Figure 8

Nonapoptotic PS signal enhances immune suppression signal in Brca1/ATP11b double-mutant primary tumors.

Options: View larger image (or click on image) Download as PowerPoint
Nonapoptotic PS signal enhances immune suppression signal in Brca1/ATP11...
(A–D) Correlation of expression of CD8 (A), ARG1 (B), and NOS2 (C) in human breast cancer patients with different expression levels of ATP11B and PTDSS2, as indicated in the NCBI-GEO database (170 patients with ATP11BhiPTDSS2hi expression, 59 patients with ATP11BhiPTDSS2lo expression, and 35 patients with ATP11BloPTDSS2hi expression), and their survival outcomes (D) (GSE21653 data set). dfs, disease-free survival. (E) Images of sections of primary tumors obtained from 545-Ctr mice and sgATP11b-545 mice stained by H&E and anti–TGF-β antibody (n = 5 mice per group). Scale bars: 50 μm. (F) Representative images of metastatic lungs by H&E, GFP, and TGF-β antibody (bottom panels) from sgATP11b-545 mice (n = 3 mice per group). Scale bars: 200 μm (upper left), 100 μm (upper right and lower left), 10 μm (lower right). Statistical data in A–C were analyzed by 1-way ANOVA with Bonferroni’s multiple-comparison test; statistical data in D were analyzed by log rank test; data are presented as mean ± SEM. *P < 0.05, ***P < 0.001.