As an adaptive response to hypoxic stress, aggressive
tumors rewire their metabolic phenotype into increased malignant behavior through extracellular
lipid scavenging and storage in lipid droplets (LD). However, the underlying mechanisms and potential
lipid source retrieved in the hypoxic tumor microenvironment remain poorly understood. Here, we show that exosome-like extracellular vesicles (EV), known as influential messengers in the tumor microenvironment, may also serve anabolic functions by transforming hypoxic, patient-derived human
glioblastoma cell lines into the LD+ phenotype. EVs were internalized via a
hypoxia-sensitive, endocytic mechanism that fueled LD formation through direct
lipid transfer, and independently of
fatty acid synthase activity. EVs can enter cells through multiple and yet ill-defined pathways. On a mechanistic level, we found that
hypoxia-mediated EV uptake depends on increased
heparan sulfate proteoglycan (
HSPG) endocytosis that preferentially followed the
lipid raft pathway. The functional relevance of
HSPG was evidenced by the reversal of EV-mediated LD loading by targeting of
HSPG receptor function. IMPLICATIONS: Together, our data extend the multifaceted role of EVs in
cancer biology by showing their LD-inducing capacity in hypoxic
glioma cells. Moreover, these findings highlight a potential function for
HSPG-mediated endocytosis as a salvage pathway for EV retrieval during
tumor stress conditions.