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Heparan sulfate N-deacetylase/N-sulfotransferase-1 regulates glioblastoma cell migration and invasion

Spyrou, Argyris ; Roy, Ananya ; Xiong, Anqi ; Kundu, Soumi ; Lu, Xi ; Jansson, Ylva ; Falk, Anna LU orcid ; Riethmüller, Christoph ; Greve, Burkhard and Götte, Martin , et al. (2025) In Matrix Biology 141. p.1-15
Abstract

The glioblastoma (GBM) microenvironment undergoes adaptations to support tumor progression, including a dysregulated extracellular matrix, with altered heparan sulfate (HS) proteoglycans. We investigated N-deacetylase/N-sulfotransferase-1 (NDST1) because NDSTs are initial modifying enzymes of HS biosynthesis and have key roles in designing the HS sulfation pattern. This, in turn governs interactions with growth factors and other biomolecules. We report that NDST1 expression is lower in GBM than in the normal brain, and that patient-derived GBM cells, grown under neural stem cell culture conditions have lower levels of HS than normal astrocytes. Overexpression of NDST1 in GBM cells with low inherent NDST1 levels stimulates cell... (More)

The glioblastoma (GBM) microenvironment undergoes adaptations to support tumor progression, including a dysregulated extracellular matrix, with altered heparan sulfate (HS) proteoglycans. We investigated N-deacetylase/N-sulfotransferase-1 (NDST1) because NDSTs are initial modifying enzymes of HS biosynthesis and have key roles in designing the HS sulfation pattern. This, in turn governs interactions with growth factors and other biomolecules. We report that NDST1 expression is lower in GBM than in the normal brain, and that patient-derived GBM cells, grown under neural stem cell culture conditions have lower levels of HS than normal astrocytes. Overexpression of NDST1 in GBM cells with low inherent NDST1 levels stimulates cell migration, reduce cell adhesion, induce EMT markers and increase invasion. Conversely, when NDST1 levels were reduced by shRNA in GBM cells, that had higher baseline expression, we find that invasion is reduced, and instead, self-renewal capacity increases alongside elevated stem cell marker expression. Moreover, overexpression of NDST1 changes chromatin accessibility of gene regulatory regions with the capacity to affect transcription factor expression, and pathways that favors cell motility and invasion. Furthermore, NDST1 overexpression results in increased activation of several receptor tyrosine kinases. This study shows that low NDST1 levels support GBM cell stemness, whereas high NDST1 levels endow tumor cells with a motile cell phenotype. We therefore propose that NDST1 is important for regulation of the balance between proliferation and invasive properties in GBM cells.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Brain tumor, Glioblastoma, Heparan sulfate, Proteoglycan, Stemness, Tumor invasion
in
Matrix Biology
volume
141
pages
15 pages
publisher
Elsevier
external identifiers
  • scopus:105013481575
  • pmid:40796061
ISSN
0945-053X
DOI
10.1016/j.matbio.2025.08.003
language
English
LU publication?
yes
id
0a0501b3-273b-46ad-9ea1-5d8d5e936d14
date added to LUP
2025-10-09 12:25:04
date last changed
2025-11-06 14:47:50
@article{0a0501b3-273b-46ad-9ea1-5d8d5e936d14,
  abstract     = {{<p>The glioblastoma (GBM) microenvironment undergoes adaptations to support tumor progression, including a dysregulated extracellular matrix, with altered heparan sulfate (HS) proteoglycans. We investigated N-deacetylase/N-sulfotransferase-1 (NDST1) because NDSTs are initial modifying enzymes of HS biosynthesis and have key roles in designing the HS sulfation pattern. This, in turn governs interactions with growth factors and other biomolecules. We report that NDST1 expression is lower in GBM than in the normal brain, and that patient-derived GBM cells, grown under neural stem cell culture conditions have lower levels of HS than normal astrocytes. Overexpression of NDST1 in GBM cells with low inherent NDST1 levels stimulates cell migration, reduce cell adhesion, induce EMT markers and increase invasion. Conversely, when NDST1 levels were reduced by shRNA in GBM cells, that had higher baseline expression, we find that invasion is reduced, and instead, self-renewal capacity increases alongside elevated stem cell marker expression. Moreover, overexpression of NDST1 changes chromatin accessibility of gene regulatory regions with the capacity to affect transcription factor expression, and pathways that favors cell motility and invasion. Furthermore, NDST1 overexpression results in increased activation of several receptor tyrosine kinases. This study shows that low NDST1 levels support GBM cell stemness, whereas high NDST1 levels endow tumor cells with a motile cell phenotype. We therefore propose that NDST1 is important for regulation of the balance between proliferation and invasive properties in GBM cells.</p>}},
  author       = {{Spyrou, Argyris and Roy, Ananya and Xiong, Anqi and Kundu, Soumi and Lu, Xi and Jansson, Ylva and Falk, Anna and Riethmüller, Christoph and Greve, Burkhard and Götte, Martin and Chen, Xinqi and Kjellén, Lena and Forsberg-Nilsson, Karin}},
  issn         = {{0945-053X}},
  keywords     = {{Brain tumor; Glioblastoma; Heparan sulfate; Proteoglycan; Stemness; Tumor invasion}},
  language     = {{eng}},
  pages        = {{1--15}},
  publisher    = {{Elsevier}},
  series       = {{Matrix Biology}},
  title        = {{Heparan sulfate N-deacetylase/N-sulfotransferase-1 regulates glioblastoma cell migration and invasion}},
  url          = {{http://dx.doi.org/10.1016/j.matbio.2025.08.003}},
  doi          = {{10.1016/j.matbio.2025.08.003}},
  volume       = {{141}},
  year         = {{2025}},
}