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

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 (ATP11B(lo)PTDSS2(hi) cells) were associated with poor prognosis and enhanced metastasis in breast cancer patients in general. Mechanistically, an ATP11B(lo)PTDSS2(hi) 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 ATP11B(lo)PTDSS2(hi) cancer cells can be effectively overcome by changing the expression phenotype to ATP11B(hi)PTDSS2(lo) through a combination of anti-PS antibody with either paclitaxel or docetaxel. Thus, blocking the ATP11B(lo)PTDSS2(hi) axis provides a new selective therapeutic strategy to prevent metastasis in breast cancer patients.