Secretion of pro‐angiogenic extracellular vesicles during hypoxia is dependent on the autophagy‐related protein GABARAPL1

Journal of Extracellular Vesicles

Sten F. Libregts¹  Marca Wauben¹  Johan Bussink²  Kasper M.A. Rouschop³  Tom G. Keulers³  Marijke I. Zonneveld³  Kim G. Savelkouls³  Joel E.J. Beaumont³  Marc Vooijs³  Carmen López‐Iglesias⁴  Hans Duimel⁴  Karel Bezstarosti⁵  Jeroen A. Demmers⁵  Ludwig Dubois⁶ 

[1] Department of Biomolecular Health Sciences Faculty of Veterinary Medicine Utrecht University Utrecht Netherlands;Department of Radiation Oncology Radboud University Medical Center Nijmegen Netherlands;Department of Radiation Oncology Radiation Oncology (Maastro) / GROW – School for Oncology and Developmental Biology Maastricht University Medical Centre + Maastricht Netherlands;Microscopy CORE Lab Maastricht Multimodal Molecular Imaging Institute FHML Division of Nanoscopy University of Maastricht Maastricht Netherlands;Proteomics Center Erasmus University Medical Center Rotterdam Netherlands;The M‐Lab Department of Precision Medicine GROW ‐ School of Oncology Maastricht University Maastricht Netherlands;

关键词: autophagy;    exosomes;    extracellular vesicles;    GABARAPL1;    hypoxia;   

DOI  :  10.1002/jev2.12166

来源: DOAJ

【 摘 要 】

Abstract Tumour hypoxia is a hallmark of solid tumours and contributes to tumour progression, metastasis development and therapy resistance. In response to hypoxia, tumour cells secrete pro‐angiogenic factors to induce blood vessel formation and restore oxygen supply to hypoxic regions. Extracellular vesicles (EVs) are emerging as mediators of intercellular communication in the tumour microenvironment. Here we demonstrate that increased expression of the LC3/GABARAP protein family member GABARAPL1, is required for endosomal maturation, sorting of cargo to endosomes and the secretion of EVs. Silencing GABARAPL1 results in a block in the early endosomal pathway and impaired secretion of EVs with pro‐angiogenic properties. Tumour xenografts of doxycycline inducible GABARAPL1 knockdown cells display impaired vascularisation that results in decreased tumour growth, elevated tumour necrosis and increased therapy efficacy. Moreover, our data show that GABARAPL1 is expressed on the EV surface and targeting GABARAPL1+EVs with GABARAPL1 targeting antibodies results in blockade of pro‐angiogenic effects in vitro. In summary, we reveal that GABARAPL1 is required for EV cargo loading and secretion. GABARAPL1+EVs are detectable and targetable and are therefore interesting to pursue as a therapeutic target.

【 授权许可】

Unknown