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^loPTDSS2^hi cells) were associated with poor prognosis and enhanced metastasis in breast cancer patients in general. Mechanistically, an ATP11B^loPTDSS2^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^loPTDSS2^hi cancer cells can be effectively overcome by changing the expression phenotype to ATP11B^hiPTDSS2^lo through a combination of anti-PS antibody with either paclitaxel or docetaxel. Thus, blocking the ATP11B^loPTDSS2^hi axis provides a new selective therapeutic strategy to prevent metastasis in breast cancer patients.

中文翻译：

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ATP11B 通过抑制非凋亡磷脂酰丝氨酸的外化抑制小鼠模型中的乳腺癌转移

癌症转移是大多数癌症相关死亡的原因。在这项研究中，我们证明了 ATP11B 的不表达或低表达与受 BRCA1 负调控的 PTDSS2 的高表达相结合，显着加速了肿瘤转移。进一步分析表明，ATP11B 低表达和 PTDSS2 高表达的细胞（ATP11B ^lo PTDSS2 ^hi细胞）通常与乳腺癌患者预后不良和转移增加有关。从机械上讲，一个 ATP11B ^lo PTDSS2 ^hi表型与细胞膜外叶非凋亡磷脂酰丝氨酸 (PS) 水平升高有关。这种 PS 增加作为一种全局免疫抑制信号，通过丰富的肿瘤微环境促进乳腺癌转移，其中髓源抑制细胞的积累和细胞毒性 T 细胞的活性降低。与 ATP11B ^lo PTDSS2 ^hi癌细胞相关的转移过程可以通过抗 PS 抗体与紫杉醇或多西紫杉醇的组合将表达表型改变为 ATP11B ^hi PTDSS2 ^{lo来有效克服。}因此，阻断 ATP11B ^lo PTDSS2 ^hi轴提供了一种新的选择性治疗策略来预防乳腺癌患者的转移。