一些癌细胞迁移和转移的特征是片状伪足突起的生长，其潜在机制仍不清楚。有证据证实板状伪足的形成可以通过多种粘附分子（例如CD44）来调节，我们之前报道过管腔型乳腺癌（BrCa）前缘的板状伪足富含CD44的高表达。在这项研究中，我们发现CD44的过度表达可以通过诱导组织型纤溶酶原激活剂（tPA）上调来促进BrCa细胞中板状伪足的形成，这是通过PI3K/Akt信号通路激活来实现的。此外，我们发现 tPA 可以与 LDL 受体相关蛋白 1 (LRP1) 相互作用，激活下游 NFκB 信号通路，进而促进板状伪足的形成。值得注意的是，抑制 tPA/LRP1-NFkB 信号级联可以减弱 CD44s 诱导的板状伪足形成。因此，我们的研究结果揭示了 CD44 在管腔 BrCa 细胞中通过 tPA/LRP1-NFkB 轴驱动板状伪足生长的新作用，这可能有助于寻找潜在的治疗靶点。版权所有 © 2023 Qiu, Wang,Guo,Liu,He,Zhang,杨、杜、高。

Some cancer cells migration and metastasis are characterized by the outgrowth of lamellipodia protrusions in which the underlying mechanism remains unclear. Evidence has confirmed that lamellipodia formation could be regulated by various adhesion molecules, such as CD44, and we previously reported that lamellipodia at the leading edge of luminal type breast cancer (BrCa) were enriched with high expression of CD44. In this study, we found that the overexpression of CD44s could promote lamellipodia formation in BrCa cells through inducing tissue type plasminogen activator (tPA) upregulation, which was achieved by PI3K/Akt signaling pathway activation. Moreover, we revealed that tPA could interact with LDL receptor related protein 1 (LRP1) to activate the downstream NFκB signaling pathway, which in turn facilitate lamellipodia formation. Notably, inhibition of the tPA/LRP1-NFkB signaling cascade could attenuate the CD44s-induced lamellipodia formation. Thus, our findings uncover a novel role of CD44s in driving lamellipodia outgrowth through tPA/LRP1-NFkB axis in luminal BrCa cells that may be helpful for seeking potential therapeutic targets.Copyright © 2023 Qiu, Wang, Guo, Liu, He, Zhang, Yang, Du and Gao.