ATP11B inhibits breast cancer metastasis in a mouse model by suppressing externalization of nonapoptotic phosphatidylserine
Jun Xu, … , Chu-Xia Deng, Xiaoling Xu
Jun Xu, … , Chu-Xia Deng, Xiaoling Xu
Published January 13, 2022
Citation Information: J Clin Invest. 2022;132(5):e149473. https://doi.org/10.1172/JCI149473.
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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

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Figure 9

Inhibition of breast cancer metastasis with combination drug treatment.

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Inhibition of breast cancer metastasis with combination drug treatment. ...
(A and B) Percentage of breast cancer patients with high or low ATP11B (A) and PTDSS2 (B) expression in the nonresponder (n = 12) and responder (n = 14) groups. (C) Percentage of patients with infiltration of tumor cells into lymph nodes from the same cohort of patients in A. (D) Protein levels of ATP11B and PTDSS2 in 628 and MDA-MB-436 cells after treatment with paclitaxel (PAC) or docetaxel (DOC) at a concentration of 2.4 nM for 5 days (n = 3). (E) Weights of tumors caused in sgATP11b/OE-Ptdss2-628 cells under various conditions including control (CON), anti-PS antibody (αPS), carboplatin (CAR), PAC, CAR+PAC+αPS, DOC, and CAR+DOC+αPS at day 21. The concentration for each drug was 5 mg/kg (body weight, 20–22 g). For single treatment, the drugs were administrated every other day. For combination treatment, the drugs were administrated twice a week, and PS antibody was given at day 7 and day 14 (200 μg per mouse) (n = 6–15 mice per group). (F and G) Quantification of GFP intensities (F) and representative images (G) with BF, GFP intensity, overlap of BF and GFP, and H&E-stained sections of lungs for mice in E (n = 6–15 mice per group). Scale bars: 2 mm; (3 mm, No treatment). (H) Heatmap of gene expression of ATP11b and Ptdss2 in breast tumor and lung tissues from the same cohort of mice in E–G (n = 6–15 mice per group). Statistical data in E and F were analyzed by 1-way ANOVA with Bonferroni’s multiple-comparison test; data are presented as mean ± SEM. ***P < 0.001.