Circulating miRNAs in Small Extracellular Vesicles Secreted by a Human Melanoma Xenograft in Mouse Brains

Abstract

The identification of liquid biomarkers remains a major challenge to improve the diagnosis of melanoma patients with brain metastases. Circulating miRNAs packaged into tumor-secreted small extracellular vesicles (sEVs) contribute to tumor progression. To investigate the release of tumor-secreted miRNAs by brain metastasis, we developed a xenograft model where human metastatic melanoma cells were injected intracranially in nude mice. The comprehensive profiles of both free miRNAs and those packaged in sEVs secreted by the melanoma cells in the plasma demonstrated that most (80%) of the sEV-associated miRNAs were also present in serum EVs from a cohort of metastatic melanomas, included in a publicly available dataset. Remarkably, among them, we found three miRNAs (miR-224-5p, miR-130a-3p and miR-21-5p) in sEVs showing a trend of upregulation during melanoma progression. Our model is proven to be valuable for identifying miRNAs in EVs that are unequivocally secreted by melanoma cells in the brain and could be associated to disease progression.

Decoding molecular programs in melanoma brain metastases

“…The cells were administered at a depth of 3 mm. The number of cells used for the inoculation was determined in accordance with previous literature with the established human melanoma cell line M14 62 . For the procedure, the animals received anesthesia (9mg Ketamine-Hydrochloride (CP-Pharma Handelsgesell- schaft mbH, Burgdorf, Germany) + 1mg Xylazine (CP-Pharma Handelsgesellschaft mbH, Burgdorf, Germany) per 100g) intraperitoneally as well as subcutaneous prophylaxis against infection (10’000 I.E, benzylpenicillin potassium, InfectoPharm Arzneimittel und Consilium GmbH, Heppenheim, Germany) and analgesia (100 mg/kg Paracetamol (B. Braun Deutschland GmbH & Co. KG, Melsungen, Germany), Lidocaine (Aspen Germany GmbH, Munich, Germany).…”

Exosomes: Small vesicles with big roles in cancer, vaccine development, and therapeutics

“…Furthermore, the results demonstrated the presence of tumor suppressor miRNAs in the total plasma, while exosome-derived miRNAs exhibited oncogenic functions. These findings suggest that cancer cells secrete tumor suppressor miRNAs into plasma and package oncogenic miRNAs in exosomes, promoting the interaction between cancer cells and their microenvironment to increase cancer cell survival and prepare a pre-metastatic niche [ 84 ].…”

MicroRNAs: emerging driver of cancer perineural invasion

“…Later, Singh et al used patient-derived stem cell lines from lung-to-brain metastases to investigate the modulatory effect of STAT3 in brain metastasis initiating cells and found STAT3 and miR-21 functioned as cooperative orchestrators of stemness and tumor initiation in lung-derived brain metastases [ 43 ]. Loredana et al demonstrated that miR-21, secreted by melanoma cells in small extracellular vesicles contributed to brain metastasis of melanoma patients [ 44 ]. These suggested that tumor cells expressing miR-21 had a disposition to migrate towards brain tissue.…”