Exosomes and EVs in tumor communication Research
In the last decade, a new type of cellular communication has been uncovered based on extracellular vesicles(EVs). EVs are secreted by most, if not all, cell types. The content of EVs varies and can include non-coding small RNAs, mRNAs, proteins and lipids. Thanks to their localization in biofluids, EVs have emerged as powerful biomarkers for several diseases, including cancer. Functionally, EVs participate in cell-cell communication between different cell types in the tumor microenvironment. EVs derived from cancer cells have been shown to favor either a pro-tumorigenic or anti-tumorigenic environment by manipulating stromal cells. Studies, including ours, showed that microRNA-containing exosomes are secreted by donor cells and are transferred to recipient cells in which microRNAs can exert their functions. The projects developed in the lab aimed to :
- Decipher the mecanism of RNA export of EVs
- Unraveling the role of exosomal non coding RNA in tumor communication
- Develop new tools to improve EV-based therapeutics
Project 1
Mechanism of RNA export in EVs
We previously initiated a project aiming to determine the impact of microRNAs secreted by the endothelium on tumor development. Depending on the tumor type and context, Evs released in the tumor microenvironement show altered content in non coding RNA. Using RNA sequencing profiling of EVs we identified several non coding RNA that are specifccaly exported during cancer.
Understanding how microRNAs and non-coding RNA are specifically exported in vesicles is currently an important question in the field that we would like to tackle in the future. Using a combination of RNA cross linking and proteomic approach we identified RNA-binding proteins involved in the export. We will continue to explore the mechanisms leading the export of other types of RNA (LncRNA, microRNA...) that we found in exosomes.
People involved : Kubra Bekar
Selected publications:
O’Grady*, T., Njock*, M.-S., Lion, M., Bruyr, J., Mariavelle, E., Galvan, B., Boeckx, A., Struman*, I., and Dequiedt*, F. (2022). Sorting and packaging of RNA into extracellular vesicles shape intracellular transcript levels. BMC Biol. 2022 201 20, 1–21.
Pérez-Boza, J., Lion, M., and Struman, I. (2018). Exploring the RNA landscape of endothelial exosomes. RNA 24, 423–435.
Pérez-Boza, J., Boeckx, A., Lion, M., Dequiedt, F., and Struman, I. (2020). hnRNPA2B1 inhibits the exosomal export of miR-503 in endothelial cells. Cell. Mol. Life Sci. 77, 4413–4428.
updated on 5/9/23
Project 2
Unraveling the role of exosomal non coding RNA in tumor communication
Image shows breast cancer cells modified to see red florescent exosomes (bleue= nucleus)
Cancer is a dynamic disease. From the initial conversion of a nonmalignant cell to a malignant cell, the developing tumor constantly evolves and generally becomes more heterogeneous during the course of the disease. Tumor heterogeneity includes not only genomic heterogeneity among neoplastic cells, but also heterogeneity of the non-cancerous compartment of the tumor microenvironment (TME), including immune, mesenchymal and endothelial cells (ECs) as well as non-cellular components. Communication within this complex environment is achieved through direct cell-cell contacts and also via secreted factors. Of these, EVs, such as exosomes, are emerging as important TME intercellular communication mediators.
In the LAM, we aim to unravel the complexity of the EV landscape in cancer. Our goal is to determine which and how some specific EV released by neoplastic cells as well as from stromal cells impact on tumorigenicity. To achieve this goal, we characterize the population of EV with a special focus on non coding RNAs and analyze their impact on tumor growth and metastasis.
People involved :Emeline Coart
Selected publications:
- Fontaine, M., Herkenne, S., Ek, O., Paquot, A., Boeckx, A., Paques, C., Nivelles, O., Thiry, M., and Struman, I. (2021). Extracellular Vesicles Mediate Communication between Endothelial and Vascular Smooth Muscle Cells. J. Mol. Sci. 2022, Vol. 23, Page 331 23, 331.
- Bovy, N., Blomme, B., Frères, P., Dederen, S., Nivelles, O., Lion, M., Carnet, O., Martial, J.A., Noël, A., Thiry, M., Jérusalem, G., Josse, C., Bours, V., Tabruyn, S.P., and Struman, I. (2015). Endothelial exosomes contribute to the antitumor response during breast cancer neoadjuvant chemotherapy via microRNA transfer. Oncotarget 6, 10253–10266.
- Halkein, J., Tabruyn, S.P., Ricke-Hoch, M., Haghikia, A., Nguyen, N.Q.N., Scherr, M., Castermans, K., Malvaux, L., Lambert, V., Thiry, M., Sliwa, K., Noel, A., Martial, J.A., Hilfiker-Kleiner, D., and Struman, I. (2013). MicroRNA-146a is a therapeutic target and biomarker for peripartum cardiomyopathy. Clin. Invest. 123, 2143–2154.
Project 3
EVs as therapeutic tools for diagnosis and treatment
Extracellular vesicles (EVs) are small vesicles secreted by all cells. Being easily accessible in plasma, EVs offers a new type of liquid-biopsy and are powerful biomarkers that can inform on tumor burden and progression. Functionally, EVs were shown to influence the tumor microenvironment as vehicles for cell–cell communication
EVs as tool for diagnosis
We recently develop a methodology allowing the detection of specific proteins the surface of EV present in the circulation. This approach offers a new way to monitor the changes of the proteins and RNA encapsulated in exosomes during tumor progression, treatment…The main advantage compared to classical biopsies is to reduced invasiveness allowing a more efficient follow-up.
Therapeutic delivery via EVs
EVs as drug delivery vehicles is a field of extensive research and development. Because they are naturally occurring, exosomes are less toxic and immunogenic than synthetic lipid nanoparticles. They offer many advantages as drug delivery vehicles: due to their small size, low immunogenicity, long half-life in the circulation, ability to load various cargos and to cross impermeable biological barriers such as the blood brain barrier. As delivery vehicle for siRNA/miRNA they protect them from degradation by blood-derived ribonucleases.
In the Lab, we explore the feasibility to use EV as a cargos for non coding RNA to treat disease. Our main projects focus on pulmonary diseases (fibrosis) and cancers (Breast, pancreas and lung).
Improving targeting
To perform its function, EVs must first bind to its recipient (or target) cell. It is known that not all EVs target the same cells but preferentially binding to some specific type of cell. This targeting ability which is inherent in EVs is a feature that could be used to specifically transport some drugs to desired cells. In the Lab we are exploring new ways to modify the targeting of EVs.
People involved : Maureen Cambier, Claire Remacle, Emeline Coart
Selected publications:
Guiot, J., Cambier, M., Boeckx, A., Henket, M., Nivelles, O., Gester, F., Louis, E., Malaise, M., Dequiedt, F., Louis, R., Struman*, I., and Njock*, M.S. (2020). Macrophage-derived exosomes attenuate fibrosis in airway epithelial cells through delivery of antifibrotic miR-142-3p. Thorax 75, 870–881.
Guiot, J., Struman, I., Louis, E., Louis, R., Malaise, M., and Njock, M.-S. (2019). Exosomal miRNAs in Lung Diseases: From Biologic Function to Therapeutic Targets. J. Clin. Med. 8, 1345.
Frères, P., Josse, C., Bovy, N., Boukerroucha, M., Struman, I., Bours, V., and Jerusalem, G. (2014). Neoadjuvant chemotherapy in breast cancer patients induces miR-34a and miR-122 expression. J. Cell. Physiol. 230, 473–481.
