Biology subjects

Ghossoub, R.

Publications and source records attributed to Ghossoub, R..

4 recordsLinked to original sources

bioRxiv2026

ADAM10 tailors extracellular vesicles for content transfer rather than signaling by contact

Etxtracellular vesicles (EVs) support cell-to-cell communication, both in physiological and pathological contexts and emerge as new biomarkers and potential therapeutics. Yet, despite EVs holding huge promises, our understanding of core mechanisms governing EV signaling remains significantly underdeveloped. Our previous work indicated that syndecans and their cytosolic adaptor syntenin control the biogenesis of a major subset of small EVs (sEVs). Here we show that syndecans control the accumulation of ADAM10 into sEVs. ADAM10 promotes the formation of sEVs enriched in cleaved receptors (reducing sEV corona), supports the sorting of proteins with intracellular functions, and tailors sEVs for the delivery of their internal content, e.g. syntenin, into the cytosol of recipient cells. Conversely, inhibition of ADAM10 favors the production of sEVs bearing full-length, signaling-competent receptors/ligands and enhances contact-dependent signaling. These findings uncover a protease-regulated switch that tailors sEV composition and signaling modality, providing important new mechanistic insights into the core molecular pathways supporting EV-mediated communication.

cell biology↗

bioRxiv2026

A syndecan-based genetic approach to coat the surface of small extracellular vesicles with Nanobodies

Small extracellular vesicles (sEVs) are promising vehicles for targeted therapeutic delivery, but strategies for their surface functionalization remain limited. Here, we present a reliable and simple genetic approach that enables customized modification of sEV surfaces and supports enhanced sEV uptake by recipient cells. This strategy is based on the fusion of targeting moieties to the C-terminal fragment of syndecan-1 (SDC1-CTF), a peptide naturally enriched in sEVs. Combining various analytical approaches including single-vesicle analysis, we establish that this strategy enables decoration of up to 20% of secreted sEVs with nanobodies (Nbs). In quantitative bioluminescence assays, using concentrated conditioned media, we demonstrate that sEV-coating with anti-EGFR Nb supports enhanced sEV uptake by EGFR-expressing cells. This new strategy thus offers a robust and modular solution for endowing sEV surfaces with defined targeting properties to support further sEV-based therapeutic applications.

cell biology↗

bioRxiv2023

Downregulation of stromal syntenin sustains AML development

The crosstalk between cancer and stromal cells plays a critical role in tumor progression. Syntenin is a small scaffold protein involved in the regulation of intercellular communication that is emerging as a target for cancer therapy. Here, we show that certain aggressive forms of acute myeloid leukemia (AML) reduce the expression of syntenin in bone marrow stromal cells (BMSC), stromal syntenin deficiency, in turn, generating a pro-tumoral microenvironment. From serial transplantations in mice and co-culture experiments, we conclude that syntenin-deficient BMSC stimulate AML aggressiveness by promoting AML cell survival and protein synthesis. This pro-tumoral activity is supported by increased expression of endoglin, a classical marker of BMSC, which in trans stimulates AML translational activity. In short, our study reveals a vicious signaling loop potentially at the heart of AML-stroma crosstalk and unsuspected tumor-suppressive effects of syntenin that need to be considered during systemic targeting of syntenin in cancer therapy.

cancer biology↗

bioRxiv2021

A syntenin-deficient microenvironment educates AML for aggressiveness

In acute myeloid leukemia (AML), the stromal microenvironment plays a prominent role in promoting tumor cell survival and progression. Although widely explored, the crosstalk between leukemic and stromal cells remains poorly understood. Syntenin, a multi-domain PDZ protein, controls both the trafficking and signaling of key molecules involved in intercellular communication. Therefore, we aimed to clarify the role of environmental syntenin in the progression of AML. By in vivo approaches in syngeneic mice, we demonstrate that a syntenin-deficient environment reprograms AML blasts to survive independently of the stroma. Up-regulation of EEF1A2 in the blasts controls this gain of cell survival. Furthermore, using ex vivo co-culture systems, we show that syntenin-deficient bone marrow stromal cells (BMSC) enhance the survival of different types of AML cells, including patient samples, and suffice to educate syngeneic AML, recapitulating micro-environmental effects observed in vivo. We establish that syntenin-deficiency causes an increase of eIF5A and autophagy-related factors in BMSC, and provide evidence that the inhibition of autophagy prevents syntenin-deficient BMSC to stimulate AML survival. Altogether, these findings indicate that host-syntenin in the BM microenvironment acts as a repressor of AML aggressiveness. Key points- A syntenin-deficient host reprograms AML blasts, enhancing total protein synthesis and cell survival pathways - Autophagy in the syntenin-deficient microenvironment is responsible for the gain of AML cell survival

cancer biology↗