Seminar

Intercepting exosome transfer in Glioblastoma by specific receptor targeting

Dr. Jordi Berenguer

Tumor progression strongly depends on the ability of cancer cells to communicate with other cancer cells and with cells from the host. The last years, extracellular vesicles (EVs), mainly comprising exosomes and shed microvesicles are gaining increasing attention as important mediators of tumor communication. EVs are secreted membranous vesicles containing active biomolecules such as (coding and non-coding) RNAs, lipids, transcription factors and cellular receptors which exert biological functions when transferred to recipient cells. Tumor cells shape their environment by exchanging secreted EVs with immune, vascular and stromal cells to suppress immune response, induce angiogenesis and extravasation, prepare pre-metastatic niches and stimulate tissue-specific migration and homing. Thus, inhibition of EV uptake represents a promising strategy to block tumor progression but, so far, EV uptake mechanisms remain largely unknown. Glioblastoma (GBM) is the most common primary tumor of the central nervous system in adults. Despite huge efforts have been made to find new therapies, standard care, which consists in tumor resection combined with radiotherapy and chemotherapy with the alkylating agent Temozolomide (TMZ), has not changed over the last decade. In this seminar it will show that GBM EVs are potent inducers of tumor cell growth and induce chemotherapy-resistant phenotype on GBM recipient cells. By means of a siRNA screen against G protein-coupled receptors, we identified the chemokine receptor CCR8 as an EV receptor. We propose a new mechanism of EV uptake in which the chemokine CCL18, a natural ligand of CCR8, acts as a bridging molecule between cellular CCR8 and proteoglycans present on the membrane of the EVs. Functional interference with this triple interaction at a receptor, ligand or glycan levels results in reduced EV uptake, and R243, a small molecule inhibitor of CCR8, is able to reduce uptake and counteracts the stimulatory effects induced by GBM EVs on cellular growth and resistance to TMZ. These findings indicate that CCR8 targeting is a feasible strategy to neutralize EV-related effects on recipient tumor cells.