Autocrine pro-legumain promotes breast cancer metastasis via binding to integrin αvβ3

• Published in: Oncogene Vol. 41; no. 34; pp. 4091 - 4103
• Main Authors: Liu, Cui, Wang, JunLei, Zheng, YaJuan, Zhu, Yue, Zhou, ZhengHang, Liu, ZhaoYuan, Lin, ChangDong, Wan, YaoYing, Wen, YaTing, Liu, ChunYe, Yuan, MengYa, Zeng, Yi Arial, Yan, ZhanJun, Ge, GaoXiang, Chen, JianFeng
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.08.2022; Nature Publishing Group
• Subjects: 13/1; 13/31; 13/89; 13/95; 631/67/322; 631/80/84; 64/60; 96/109; Apoptosis; Autocrine signalling; Breast cancer; Breast Neoplasms - pathology; Cell adhesion & migration; Cell Biology; Cell Line, Tumor; Cell migration; Cell Proliferation; Cell surface; Cysteine Endopeptidases; Cysteine proteinase; Female; Human Genetics; Humans; Integrin alphaVbeta3 - genetics; Integrin alphaVbeta3 - metabolism; Internal Medicine; Legumain; Medicine; Medicine & Public Health; Metastases; Metastasis; Monoclonal antibodies; Neoplasm Metastasis; Oligopeptides; Oncology; Proenzymes; RhoA protein; Tumors
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-022-02409-4

Tumor metastasis is the leading cause of cancer-associated mortality. Unfortunately, the underlying mechanism of metastasis is poorly understood. Expression of legumain (LGMN), an endo-lysosomal cysteine protease, positively correlates with breast cancer metastatic progression and poor prognosis. Here, we report that LGMN is secreted in the zymogen form by motile breast cancer cells. Through binding to cell surface integrin αvβ3 via an RGD motif, the autocrine pro-LGMN activates FAK-Src-RhoA signaling in cancer cells and promotes cancer cell migration and invasion independent of LGMN protease activity. Either silencing LGMN expression or mutationally abolishing pro-LGMN‒αvβ3 interaction significantly inhibits cancer cell migration and invasion in vitro and breast cancer metastasis in vivo. Finally, we developed a monoclonal antibody against LGMN RGD motif, which blocks pro-LGMN‒αvβ3 binding, and effectively suppresses cancer cell migration and invasion in vitro and breast cancer metastasis in vivo. Thus, disruption of pro-LGMN‒integrin αvβ3 interaction may be a potentially promising strategy for treating breast cancer metastasis.