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 7

TME in mammary tissues with expression of sgATP11b and sgATP11b/OE-Ptdss2.

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TME in mammary tissues with expression of sgATP11b and sgATP11b/OE-Ptdss...
(A) Top 10 activated pathways based on gene expression profiles of RNA-Seq from metastatic lungs compared with those of normal lungs (n = 4 mice per group) by the GO enrichment analysis in the clusterProfiler package (https://bioconductor.org/packages/release/bioc/html/clusterProfiler.html). (B) Master regulatory gene analysis of the immune gene transcriptional network established by the RTN package. The immune genes (red) and master regulatory genes (green) were extracted from the GSE54219 data set and analyzed by master regulatory analysis (MRA) (76 patients in BRCA1-WT group and 47 patients in BRCA1-MT group). Genes that are positively (red line) or negatively (blue line) regulated by PS-related genes are indicated. The P value of ATP11B as the master regulatory gene of immune cells is 0.0021. (C) Profiles of MDSC populations from mammary tumors implanted with 545 cells with indicated modifications in nude mice analyzed with antibodies against CD45, CD11B, Ly6G, and Ly6C by CyTOF analysis (n = 3 mice per group). (D) Quantification of MDSC, PMN-MDSC, and monocytic MDSC (MO-MDSC) populations in C. (E and F) Representative CFSE flow cytometry histograms showing inhibitive effect of MDSCs isolated from the spleen of tumor-bearing mice implanted with Ctr-545 or sgATP11b-545 cells on the proliferation of T cells stimulated with anti-CD3/anti-CD28 antibody obtained from WT mice (E), and summarized results (F) (n = 3 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 < 0.001.