Lipid Droplets Fuel Small Extracellular Vesicle Biogenesis

Abstract
Despite an increasing gain of knowledge regarding small extracellular vesicle (sEV) composition and functions in cell-cell communication, the mechanism behind their biogenesis remains unclear. Here, we revealed for the first time that the sEV biogenesis and release into the microenvironment are tightly connected with another important organelle: Lipid Droplets (LD). We have observed this correlation using different human cancer cell lines as well as patient-derived colorectal cancer stem cells (CR-CSCs). Our results showed that the use of external stimuli such as radiation, pH, hypoxia, or lipid interfering drugs, known to affect the LD content, had a similar effect in terms of sEV secretion. Additional validations were brought using multiple omics data, at the mRNA and protein levels. Altogether, the possibility to fine-tune sEV biogenesis by targeting LDs, could have a massive impact on the amount, the cargos and the properties of those sEVs, paving the way for new clinical perspectives.

Citation
Genard, G., Tirinato, L., Pagliari, F., Da Silva, J., Giammona, A., Alquraish, F., Bordas, M., Marafioti, M. G., Di Franco, S., Jansen, J., Garcia-Calderon, D., Hanley, R., Nistico, C., Fukasawa, Y., Mueller, T., Krijgsveld, J., Todaro, M., Costanzo, F. S., Stassi, G., … Seco, J. (2022). Lipid Droplets Fuel Small Extracellular Vesicle Biogenesis. https://doi.org/10.1101/2022.10.24.513202

Acknowledgements
We gratefully acknowledge the imaging and FACS Facilities at the DKFZ and the CoreLab Genomic Facility at KAUST for their prompt and precious support. We also are grateful to the Dr. Sebastian Dieter’s group for the continuous access to the ultracentrifuge. Carlo Liberale and Joao Seco acknowledge funding from King Abdullah University of Science and Technology, Grant Award Number: OSR-CRG2018-3747. Luca Tirinato has received funding from AIRC and from the European Union’s Horizon 2020 Research and Innovation Programme under the Marie Sklodowska-Curie grant agreement n. 793 800924. Jeannette Jansen was supported by grants of the German-Israeli Helmholtz Research School in Cancer Biology – Cancer Transitional and Research Exchange Program (Cancer-TRAX). Daniel Garcia-Calderon was funded by the Graduate School Scholarship Programme, 2019 from the DAAD.

Publisher
Cold Spring Harbor Laboratory

DOI
10.1101/2022.10.24.513202

Additional Links
http://biorxiv.org/lookup/doi/10.1101/2022.10.24.513202

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