Identification of the SNARE complex that mediates the fusion of multivesicular bodies with the plasma membrane in exosome secretion

Abstract Exosomes play crucial roles in local and distant cellular communication and are involved in various physiological and pathological processes. Tumour‐derived exosomes are pivotal to tumorigenesis, but the precise mechanisms underlying their secretion remain elusive. In particular, the SNARE proteins that mediate the fusion of multivesicular bodies (MVBs) with the plasma membrane (PM) in tumour cells are subject to debate. In this study, we identified syntaxin‐4, SNAP‐23, and VAMP‐7 as the SNAREs responsible for exosome secretion in MCF‐7 breast cancer cells and found that a SNARE complex consisting of these SNAREs can drive membrane fusion in vitro. Deletion of any of these SNAREs in MCF‐7 cells did not affect MVB biogenesis and transportation, indicating their specific involvement in MVB–PM fusion. In addition, syntaxin‐4, SNAP‐23, and VAMP‐7 play equivalent roles in exosome secretion in both HeLa cervical cancer cells and A375 melanoma cells, suggesting their conserved function in exosome secretion. Furthermore, deletion of VAMP‐7 in 4T1 mammary carcinoma cells efficiently inhibited exosome secretion and led to significant attenuation of tumour growth and lung metastasis in mouse models, implying that VAMP‐7 may hold promise as a novel therapeutic target for breast cancer.