Extracellular Vesicles Derived from SIPA1high Breast Cancer Cells Enhance Macrophage Infiltration and Cancer Metastasis through Myosin-9

Abstract

Tumour cell metastasis can be genetically regulated by proteins contained in cancer cell-derived extracellular vesicles (EVs) released to the tumour microenvironment. Here, we found that the number of infiltrated macrophages was positively correlated with the expression of signal-induced proliferation-associated 1 (SIPA1) in invasive breast ductal carcinoma tissues and MDA-MB-231 xenograft tumours. EVs derived from MDA-MB-231 cells (231-EVs) significantly enhanced macrophage migration, compared with that from <i>SIPA1</i>-knockdown MDA-MB-231 cells (231/si-EVs) both in vitro and in vivo. We revealed that SIPA1 promoted the transcription of <i>MYH9</i>, which encodes myosin-9, and up-regulated the expression level of myosin-9 in breast cancer cells and their EVs. We also found that blocking myosin-9 by either down-regulating SIPA1 expression or blebbistatin treatment led to the suppression of macrophage infiltration. Survival analysis showed that breast cancer patients with high expression of <i>SIPA1</i> and <i>MYH9</i> molecules had worse relapse-free survival (<i>p</i> = 0.028). In summary, SIPA1^high breast cancer can enhance macrophage infiltration through EVs enriched with myosin-9, which might aggravate the malignancy of breast cancer.