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 6

ATP11bloPTDSS2hi expression enhances breast cancer metastasis.

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ATP11bloPTDSS2hi expression enhances breast cancer metastasis. (A) Repre...
(A) Representative metastatic images of primary breast tumor, lung, ovary, kidney, and abdominal fat from a 7-month-old Brca1-Trp53-MSK female mouse after intraductal injection of mixed sgATP11b and Ptdss2-GFP lentiviruses (n = 5 mice). Scale bars: 2.548 mm (R4 BT), 0.277 mm (lung), 0.3612 mm (ovary), 0.4676 mm (kidney), 0.9263 mm (abdominal fat). (B) Validation of sgATP11b DNA in primary tumor tissues and metastatic tissues, including lung, liver, ovary, kidney, and abdominal fat tissues, as determined with specific primers for ATP11b by PCR. (C and D) PS displacement in 545 and 628 cells without or with sgATP11b expression by FACS analysis with PS antibody. (D) Quantification of PS on the outer cell membrane in C (n = 3). (E) Protein levels of ATP11B in 545, 628, and MDA-MB-436 cells without or with sgATP11b expression by Western blot (n = 3). (F) Protein levels of ATP11B and PTDSS2 in 545 and 628 cells without or with sgPtdss2, OE-ATP11b, OE-ATP11b/sgPtdss2, or sgATP11b/OE-Ptdss2 expression by Western blot (n = 3). (G) Representative images of PS displacement in/on the membranes of 628 cells without or with sgATP11b, OE-Ptdss2, sgATP11b/OE-Ptdss2, or OE-ATP11b/sgPtdss2 expression by immunofluorescence staining with an anti-PS antibody (red), imaged by super-resolution microscopy (n = 3). Scale bars: 5 μm. (H) Representative lung bright-field (BF) images, GFP signal, and overlapped images showing the BF and GFP signals in nude mice without implantation (WT) and 3 weeks after mammary fat pad implantation with 628 parental cells or 628 cells expressing sgAT11b, or with OE-ATP11b in sgATP11b cells, or sgATP11b/OE-Ptdss2, or OE-ATP11b/sgPtdss2 (n = 3). Scale bars: 3 mm. (I and J) Quantification for lung volumes (I) and GFP intensities (J) from the same cohort of mice shown in H (n = 8 mice per group). Statistical data in D were analyzed by 1-way ANOVA with Bonferroni’s multiple-comparison test; data are presented as mean ± SEM. *P < 0.05, **P < 0.01.