While interest in EVs has exploded in the biomedical sciences (as a source of biomarkers and for innovative therapies), our knowledge of the mechanisms by which EVs are formed, released and captured by cells is still very limited. Our previous studies have shown that syndecans function in the formation and capture of EVs, notably in coordination with tetraspanins and certain PDZ-domain proteins. We were able to establish that syndecan sugars and proteins must be cleaved to enable EV biogenesis, while uncleaved syndecans function in EV capture. Here, we aim to investigate the role of syndecan processing in EV trafficking, contact signaling, capture and cargo delivery.

Remodeling of the extracellular matrix (ECM) is essential for tumor progression. Secreted and transmembrane matrix metalloproteinases (MMPs) are the main proteases controlling the degradation and activity of ECM components. They participate in the remodeling of the ECM, eliminating barriers and thus facilitating cell migration and invasion.

MMPs have been identified as components of EVs. However, the molecular mechanisms by which they load into EVs and the role of EV-associated MMPs in matrix invasion are poorly understood. Transmembrane MMPs have a PDZ-binding motif at the C-terminus of their intracellular domain. We are evaluating the impact of PDZ-domain proteins, including Syntenin, on the loading of transmembrane MMPs into EVs and on ECM degradation by EVs.

Secretory autophagy is secretion from endosomal compartments created (in part) using "autophagy proteins" or components also used in classical "degradative" autophagy (leading to cargo destruction). Secretory autophagy occurs when autophagic structures fuse with the plasma membrane instead of the lysosome. Thus, secretory autophagy includes EV secretion, but is not limited to EVs. For example, some cytokines are secreted from "autophagic" compartments but freely, i.e. not enclosed in EVs. Syntenin EV secretion from early/late endosomes, as far as we know, does not depend on proteins involved in autophagy. Here, we aim to determine whether and how syntenin regulates autophagy-dependent secretion.

Acute myeloid leukemia (AML) has a 60% relapse rate after treatment, and its heterogeneity limits the efficacy of targeted therapies. Therapeutic failure is attributed to the persistence of leukemic stem cells (LSC), protected by bone marrow stromal cells (BMSC). Targeting BMSC/LSC (stroma/tumor) exchanges could improve treatment efficacy.

Our data suggest that in AML, syntenin expression is up-regulated in tumor cells and down-regulated in BMSCs. This project aims to elucidate how "low-syntenin" BMSCs and "high-syntenin" tumor cells influence AML strain, assess the role of syntenin in microenvironment remodeling, and evaluate the therapeutic potential of pharmacological inhibitors (developed in our lab and targeting PDZ2 involved in syndecan binding) of syntenin functions. This project will establish the role of syntenin in stroma-tumor communication and its relevance as a therapeutic target for preventing AML relapse.

In collaboration with the team of Prof. Eline MENU and Chenggong TU (PhD student) (HEIM - VUB, Brussels), we are also investigating the therapeutic potential of our syntenin inhibitors in the treatment of multiple myeloma.

Antibody-drug conjugates (ADCs) are new treatments that have considerably improved cancer care. However, resistance mechanisms to ADCs are emerging, limiting their efficacy. This project explores protease inhibition as a strategy for enhancing ADC activity and overcoming resistance mechanisms.

This work is being carried out in collaboration with Dr Alexandre De Nonneville (Institut Paoli-Calmettes) and benefits from privileged access to a large cohort of patients at different stages of breast cancer (PerMED trial - IPC).

Here, we aim to clarify whether genetic and synthetic biology approaches, taking advantage of the mechanistic insights into EV-based signaling revealed by the laboratory, can aid the development of EV-based therapies.

In collaboration with the team of Prof. Elke DE BRUYNE and Michiel DE COSTER (PhD student) (HEIM - VUB, Brussels), we are investigating the potential of our modified EVs for the treatment of multiple myeloma. In collaboration with Patrick CHAMES' team (CRCM), we are developing nanobodies to enhance EV uptake by target cells.