CD44s-activated tPA/LRP1-NFκB pathway drives lamellipodia outgrowth in luminal-type breast cancer cells

Yaqi Qiu; Hui Wang; Qian Guo; Yiwen Liu; Yiqing He; Guoliang Zhang; Cuixia Yang; Yan Du; Feng Gao

doi:10.3389/fcell.2023.1224827

CD44s-activated tPA/LRP1-NFκB pathway drives lamellipodia outgrowth in luminal-type breast cancer cells

Front Cell Dev Biol. 2023 Sep 28:11:1224827. doi: 10.3389/fcell.2023.1224827. eCollection 2023.

Authors

Yaqi Qiu^#^{1

2}, Hui Wang^#^{1

2}, Qian Guo¹, Yiwen Liu¹, Yiqing He¹, Guoliang Zhang¹, Cuixia Yang^{1

2}, Yan Du¹, Feng Gao^{1

2}

Affiliations

¹ Department of Molecular Biology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Department of Clinical Laboratory, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.

^# Contributed equally.

Abstract

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.

Keywords: CD44; LRP1; TPA; lamellipodia; luminal type breast cancer.

Grants and funding

This work was supported by the National Natural Science Foundation of China (82273462, 82073199, 81974445, 81974446, 81872357, and 81702852), Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (20171924), Shanghai Pujiang Program (2019PJD037) and Shanghai Rising Stars of Medical Talent Youth Development Program Clinical Laboratory Practitioners Program (2020_087, 2021_099).