4.7 Article

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

期刊

JOURNAL OF EXTRACELLULAR VESICLES
卷 10, 期 14, 页码 -

出版社

WILEY
DOI: 10.1002/jev2.12166

关键词

autophagy; exosomes; extracellular vesicles; GABARAPL1; hypoxia

资金

  1. KWF Kankerbestrijding [UM2012-5506, 2015-7735, 12276]
  2. Worldwide Cancer Research [16-0265]
  3. Stichting Zeldzame Ziekten

向作者/读者索取更多资源

GABARAPL1 is essential for cargo loading and secretion of extracellular vesicles, with GABARAPL1(+)EVs being detectable and targetable for blocking pro-angiogenic effects. Silencing GABARAPL1 results in impaired early endosomal pathway and secretion of EVs with pro-angiogenic properties, affecting tumor growth and therapy efficacy.
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.

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