Roles of extracellular vesicles and their microRNA cargo in chemotherapeutic resistance, pro-coagulant phenotype and as potential biomarkers in diffuse large B-cell lymphoma

Promoters

Prof. Jean-Michel DOGNE, UNamur, Department of Pharmacy (promoter)

Prof. Christian CHATELAIN, CHU UCL Namur, Hematology department (co-promoter)

Jury

Nathalie CARON, UNamur ; Jean-Michel DOGNE, UNamur ; Christian CHATELAIN, UNamur ; Carlos GRAUX, UCL ; Carine MICHIELS, UNamur ; Basile STAMATOPOULOS, ULB ; Ingrid STRUMAN, Ulg.

Summary

Considered in the past as cell debris or artifacts, extracellular vesicles (EVs) play a role in intercellular communication forming a delivery system enabling cells to exchange cellular material. Among the biological molecules potentially transferred by EVs, microRNAs are able to modify the target cell phenotype. The intercellular communication via EVs plays a major role in cancer by facilitating cellular material exchange among cancer cells and between cancer cells and their microenvironment. EVs circulate in all biological fluids. For this reason, a lot of studies try to use them as biomarkers. The objectives of this PhD thesis were first to investigate the roles of EVs and their microRNA cargo in two complications impacting survival of cancer patients: thrombosis and chemo-resistance. In a second time, we evaluated the use of circulating microRNAs from plasma as biomarkers in diffuse large B-cell lymphoma (DLBCL).
This project began with a literature review on the contribution of EVs to the pro-coagulant phenotype of cancer patients. Particularly, we hypothesized that EVs are able to interact with vascular endothelial cells and induce a pro-coagulant switch of these physiological anti-coagulant surfaces. In a second study, we demonstrated in vitro that EVs are able to mediate the transfer some chemo-resistance characteristics from a multidrug resistant cell line to its sensitive counterpart. This PhD thesis ended with an analysis of the microRNAs circulating in plasma from DLBCL patients and highlighted five microRNAs that would reveal tumor evolution in patients. In conclusion, our results on the roles of EVs in chemo-resistance and in pro-coagulant phenotype of cancer patients demonstrate their impact on some key parameters of tumorigenesis. These results add new arguments for the use of EVs as treatment targets. EVs could also be used as biomarkers as highlighted by our study on circulating microRNAs in plasma.