492P - Wound stress stimulation promotes lung metastasis of breast cancer by regulating CXCL12/CXCR4 axis through MDSC exosome miR-126a-5p

Background

Surgery is one of the necessary treatment methods for breast cancer patients. However, wound caused by surgery is the main source of clinically related stress stimulation, and can promote tumor metastasis. Currently, as an important component of the tumor microenvironment, myeloid-derived suppressor cells (MDSC) have become a hotspot in the study of tumor metastasis.

Methods

We comprehensively explored the influence of wound stress on tumor growth, EMT related metastasis, and the recruitment of MDSC in the tumor microenvironment in a subcutaneous 4T1 tumor model.

Results

We found that wound stress stimulation promoted breast cancer growth and lung metastasis in mice, and enhanced the recruitment of stressed MDSC in the tumor microenvironment. The expression of Vimentin increased, suggesting EMT transformation. In vitro, bone marrow MDSC cells from mice undertaking stress stimulation promoted the EMT transformation in 4T1. The exosomes were extracted and the expression of mmu-miR-126a-5p was low in stressed MDSC exosomes. Mmu-miR-126a-5p overexpression suppressed tumor growth, lung metastasis and EMT transformation. Through the database screening of the target gene of mmu-miR-126a-5p combined with the results of sequencing analysis, CXCL12 was predicted to be the target gene of mmu-miR-126a-5p, which was verified by double luciferase reporting assay. CXCL12 and CXCR4 were highly expressed in the wound stress stimulation model, indicating mmu-miR-126a-5p induces breast cancer EMT transformation by targeting CXCL12/CXCR4 axis.

Conclusions

Here, we found that surgical stress stimulation can elicit the recruitment of stressed MDSC in the tumor microenvironment. Reduced exosome miR-126a-5p released by stressed MDSC leads to EMT transformation of tumor cells by attenuating the inhibition of CXCL12/CXCR4 axis in 4T1 cells and ultimately promotes increased lung metastasis. From the perspective of tumor microenvironment, these findings explain the phenomenon of increased lung metastasis caused by surgical stress stimulation and optimize new targets for MDSC, thus providing new ideas for breast cancer treatment.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.