Tumor-derived HMGB1 induces CD62Ldim neutrophil polarization and promotes lung metastasis in triple-negative breast cancer

Zhen Wang,Liyun Shi,Lili Li,Ke Su,Jun Yan,Haiyan Zheng,Chenghui Yang,Xiaoyan Jin,Zhigang Zhang,Zhou Jiang,Baizhou Li,Jun Pan,Fuming Qiu,Jian Huang,Xuan Shao

doi:10.1038/s41389-020-00267-x

Abstract

Triple-negative breast cancer (TNBC) is highly aggressive, difficult to treat and commonly develops visceral metastasis, including lung metastasis. We observed that High mobility group box 1 protein (HMGB1) was highly expressed in human TNBC and positively correlated with cancer metastasis. The hypoxic tumor environment is known to regulate HMGB1 secretion, but an understanding of the underlying mechanism by which tumor-derived HMGB1 regulates interstitial components and promotes breast cancer lung metastasis has remained elusive. The results of the present study showed that the number of CD62Ldim neutrophils, which have a strong ability to produce neutrophil extracellular traps (NETs), increased significantly in both peripheral blood and lung tissues in a mouse TNBC model and were regulated by tumor-derived HMGB1 through the TLR2 pathway. Furthermore, serum HMGB1 levels were positively correlated with CD62Ldim neutrophils in 86 breast cancer patients. We demonstrated that CD62Ldim neutrophils accelerated lung metastasis and that interventions targeting the “HMGB1-CD62Ldim neutrophil-NETs” axis could inhibit lung metastasis. Our results suggest that the combination of HMGB1 and CD62Ldim neutrophils is a potential marker for breast cancer lung metastasis and is novel target for future prevention and therapy.

Highlights

Breast cancer is one of the most common malignant tumors worldwide
We tested the serum of 86 patients and observed that the serum High mobility group box 1 protein (HMGB1) level was significantly increased in Triple-negative breast cancer (TNBC) patients (Fig. 1f)
These results suggest that HMGB1 is closely associated with tumor metastasis in breast cancer, especially in TNBC

Summary

Introduction

Breast cancer is one of the most common malignant tumors worldwide. Its morbidity ranks first among women, and its mortality rate ranks third[1]. The primary cause of death in breast cancer patients is distant organ metastasis. Triple-negative breast cancer (TNBC) has the worst prognosis of breast cancers and preferentially metastasizes to the lung[2]. There is currently no definite marker to predict tumor metastasis. HMGB1 is a highly conserved nuclear protein that was discovered in the calf thymus and consists of two DNA-

Methods

Results

Conclusion