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Hypoxic induction of exosome uptake through proteoglycan-dependent endocytosis fuels the lipid droplet phenotype in Glioma

Cerezo-Magaña, Myriam LU orcid ; Christianson, Helena C. LU ; van Kuppevelt, Toin H. ; Forsberg-Nilsson, Karin and Belting, Mattias LU (2021) In Molecular Cancer Research 19(3). p.528-540
Abstract

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 LDþ phenotype. EVs were internalized via a hypoxia-sensitive, endocytic mechanism that fueled LD formation through direct lipid transfer, and independently of... (More)

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 LDþ 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.

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author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Molecular Cancer Research
volume
19
issue
3
pages
13 pages
publisher
American Association for Cancer Research
external identifiers
  • scopus:85099679029
  • pmid:33288734
ISSN
1541-7786
DOI
10.1158/1541-7786.MCR-20-0560
language
English
LU publication?
yes
id
361a813c-b831-4c97-b38b-463e9941e6e4
date added to LUP
2022-03-03 16:48:25
date last changed
2024-06-27 12:25:15
@article{361a813c-b831-4c97-b38b-463e9941e6e4,
  abstract     = {{<p>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<sup>þ</sup> 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.</p>}},
  author       = {{Cerezo-Magaña, Myriam and Christianson, Helena C. and van Kuppevelt, Toin H. and Forsberg-Nilsson, Karin and Belting, Mattias}},
  issn         = {{1541-7786}},
  language     = {{eng}},
  month        = {{03}},
  number       = {{3}},
  pages        = {{528--540}},
  publisher    = {{American Association for Cancer Research}},
  series       = {{Molecular Cancer Research}},
  title        = {{Hypoxic induction of exosome uptake through proteoglycan-dependent endocytosis fuels the lipid droplet phenotype in Glioma}},
  url          = {{http://dx.doi.org/10.1158/1541-7786.MCR-20-0560}},
  doi          = {{10.1158/1541-7786.MCR-20-0560}},
  volume       = {{19}},
  year         = {{2021}},
}