Analysing novel mechanisms involved in tumour-adipose tissue crosstalk during melanoma metastasis: role of secreted exosomes and soluble factors

• Published in: Journal of extracellular vesicles Vol. 7; p. 232
• Main Authors: de Lope, Lucía Robado, Benito-Martin, Alberto, Sánchez-Redondo, Sara, Megias, Diego, Hergueta-Redondo, Marta, Peinado, Héctor
• Format: Journal Article
• Language: English
• Published: Abingdon John Wiley & Sons, Inc 01.01.2018
• Subjects: Adipose tissue; Animal models; Cancer; Chemokines; Cytokines; Exosomes; Flow cytometry; High fat diet; Melanoma; Mesenchyme; Metastases; Metastasis; Obesity; Secretome; Stem cell transplantation; Stem cells; Tumors
• ISSN: 2001-3078

Background: Increasing evidences reveal a link between obesity and the development and progression of certain types of cancer. However, the implication of obesity in melanoma metastasis is not well known. Recent data support a role for secreted factors [e.g. soluble factors and extracellular vesicles] in the communication between tumour cells and adipose tissue during metastasis. Still, the specific factors reinforcing the metastatic behaviour have not been defined yet. Methods: Mice under regular and high fat diet (HFD) were intravenously injected with melanoma cells to analyse their metastatic behaviour in both conditions. In addition, we isolated adipose tissue from control and HFD mice to analyse the secretome of different fat depots. We also performed in vitro and in vivo approaches to determine the uptake of exosomes by adipose tissue. Flow cytometry analysis was done after the in vivo injection of tumour-derived exosomes in control and HFD mice. In vitro analysis was performed using the Opera High Content Screening System. We analysed the phenotypic changes promoted by tumour-derived exosomes in adipose tissue-derived mesenchymal stem cells (AD-MSCs). Results: We found that HFD-fed mice had increased metastatic burden in specific anatomical locations of adipose tissue (e.g. inguinal, retroperitoneal) compared to controls. To decipher the factors involved, we analysed adipose tissue-secreted exosomes and soluble factors and found that some cytokines were highly secreted in the HFD group, which may be involved in metastatic cell homing. In addition, we found that tumour-secreted exosomes home to adipose tissue depots and are uptaken by AD-MSCs. Particularly, AD-MSCs from HFD mice increased their ability to uptake exosomes in vivo. In vitro analysis suggests that tumour-derived exosomes from highly malignant models impair lipid accumulation in AD-MSCs. Summary/Conclusion: Our data show that chemokines secreted by different adipose tissue depots may favour metastatic seeding. Moreover, we propose that tumour-secreted exosomes are a novel mechanism of communication between tumour and AD-MSCs impairing their function and reinforcing metastatic behaviour.