Exosomes are small vesicles, 30-150 nm in diameter, released from all cells in the body. It has been shown that circulating exosomes released from cancers increase metastatic spread within the body, including to the brain.
Exosomes released from the primary tumour into circulation can communicate with and activate normal cells in secondary organs before circulating tumour cells arrive at these sites. MiRNAs, which are small non-coding RNAs of 18-24 nucleotides in length, represent the major RNA component in exosomes. Exosome-derived miRNAs have already been shown to exert tumour-promoting functions in preparing pre-metastatic niches.
The mechanistic engagement of miRNAs in facilitating melanoma brain metastasis (MBM) remains largely unknown. We are focusing on the role of exosome-derived miRNAs in the development of MBM. Our main hypothesis is that a novel treatment for MBM can be established, by modulating the expression levels of miRNAs in the brain metastatic environment.
We have already shown that exosome pretreatment of mice increases brain metastatic burden in the animal brains, when tumour cells are injected into the bloodstream 3 days after pretreatment (top figure). We have also found that knock-down (KD) of a specific miRNA results in an inhibition of brain metastatic growth (lower figure).
We are now performing bioinformatics analysis, to determine signaling pathways which may be affected by this miRNA. We are also performing in silico docking analysis to determine candidate drugs which may inhibit the transcription of this miRNA. We will test these drugs in vitro and in vivo, with the aim of bringing one of the candidates forward into the clinic.