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

• Published in: The Journal of clinical investigation Vol. 132; no. 5; pp. 1 - 19
• Main Authors: Xu, Jun, Su, Sek Man, Zhang, Xin, Chan, Un In, Adhav, Ragini, Shu, Xiaodong, Liu, Jianlin, Li, Jianjie, Mo, Lihua, Wang, Yuqing, An, Tingting, Lei, Josh Haipeng, Miao, Kai, Deng, Chu-Xia, Xu, Xiaoling
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.03.2022
• Subjects: Animals; Biomedical research; BRCA1 protein; Breast cancer; Breast Neoplasms - metabolism; Cancer; Care and treatment; Cell Line, Tumor; Cell membranes; CRISPR; Cytotoxicity; Female; Gene expression; Genetic aspects; Genomes; Health aspects; Humans; Lymphocytes T; Medical prognosis; Melanoma; Melanoma, Cutaneous Malignant; Metastases; Metastasis; Mice; Molecular targeted therapy; Mutation; Myeloid-Derived Suppressor Cells - pathology; Neoplasm Metastasis - pathology; Neoplasms, Second Primary - pathology; Oncology; Oncology, Experimental; Paclitaxel; Phenotypes; Phosphatidylserine; Phosphatidylserines; Phospholipids; Skin Neoplasms; Suppressor cells; Tumor Microenvironment; Tumor suppressor genes; Tumorigenesis; Tumors; China; Oncology; Breast cancer; Cancer immunotherapy; Tumor suppressors
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI149473

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.