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Pericytes orchestrate a tumor-restraining microenvironment in glioblastoma

Braun, Sebastian LU ; Bolivar, Paulina LU ; Oudenaarden, Clara ; Sjölund, Jonas LU orcid ; Bocci, Matteo LU orcid ; Harbst, Katja LU orcid ; Talkhoncheh, Mehrnaz Safaee LU ; Phung, Bengt LU ; Cordero, Eugenia LU and Rosberg, Rebecca LU orcid , et al. (2025) In Nature Communications 16(1).
Abstract

Glioblastoma (GBM) is characterized by fast progression, infiltrative growth pattern, and a high relapse rate. A defining feature of GBM is the existence of spatially and functionally distinct cellular niches, where malignant cells engage in paracrine crosstalk with cell types comprising the tumor microenvironment. Here, we identify pericytes as the most active paracrine signaling hub within the tumor parenchyma. Their depletion through genetic engineering results in accelerated tumor progression and shortened survival. Mechanistic studies reveal that pericyte deficiency remodels the endothelium and impacts the immune cell landscape, exacerbating tumor cell invasion and immune suppression. Specifically, the pericyte-deprived endothelium... (More)

Glioblastoma (GBM) is characterized by fast progression, infiltrative growth pattern, and a high relapse rate. A defining feature of GBM is the existence of spatially and functionally distinct cellular niches, where malignant cells engage in paracrine crosstalk with cell types comprising the tumor microenvironment. Here, we identify pericytes as the most active paracrine signaling hub within the tumor parenchyma. Their depletion through genetic engineering results in accelerated tumor progression and shortened survival. Mechanistic studies reveal that pericyte deficiency remodels the endothelium and impacts the immune cell landscape, exacerbating tumor cell invasion and immune suppression. Specifically, the pericyte-deprived endothelium recruits perivascular, tumor-associated macrophages polarized towards an immune-suppressive phenotype. The recruited macrophages express Hepatocyte Growth Factor, which reinforces activation of its receptor tyrosine kinase MET on GBM cells harboring a pronounced mesenchymal subtype driven by the key phenotypic regulator Fosl1. Indeed, orthotopic implantation of MET-expressing GBM cells corroborates their superior tumor-initiating and invasive capabilities. Thus, pericytes represent critical modulators of GBM development by orchestrating a tumor-suppressive microenvironment, highlighting the importance of their preservation in therapy.

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publication status
published
subject
keywords
Pericytes/metabolism, Glioblastoma/pathology, Tumor Microenvironment/immunology, Humans, Animals, Brain Neoplasms/pathology, Mice, Cell Line, Tumor, Proto-Oncogene Proteins c-met/metabolism, Hepatocyte Growth Factor/metabolism, Paracrine Communication, Proto-Oncogene Proteins c-fos/metabolism, Tumor-Associated Macrophages/metabolism, Macrophages/metabolism
in
Nature Communications
volume
16
issue
1
article number
10918
pages
22 pages
publisher
Nature Publishing Group
external identifiers
  • pmid:41339360
ISSN
2041-1723
DOI
10.1038/s41467-025-66985-1
language
English
LU publication?
yes
additional info
© 2025. The Author(s).
id
ff18a4fa-d70f-43cf-a7b3-f6da9e6e34f0
date added to LUP
2025-12-08 09:22:53
date last changed
2025-12-08 11:59:37
@article{ff18a4fa-d70f-43cf-a7b3-f6da9e6e34f0,
  abstract     = {{<p>Glioblastoma (GBM) is characterized by fast progression, infiltrative growth pattern, and a high relapse rate. A defining feature of GBM is the existence of spatially and functionally distinct cellular niches, where malignant cells engage in paracrine crosstalk with cell types comprising the tumor microenvironment. Here, we identify pericytes as the most active paracrine signaling hub within the tumor parenchyma. Their depletion through genetic engineering results in accelerated tumor progression and shortened survival. Mechanistic studies reveal that pericyte deficiency remodels the endothelium and impacts the immune cell landscape, exacerbating tumor cell invasion and immune suppression. Specifically, the pericyte-deprived endothelium recruits perivascular, tumor-associated macrophages polarized towards an immune-suppressive phenotype. The recruited macrophages express Hepatocyte Growth Factor, which reinforces activation of its receptor tyrosine kinase MET on GBM cells harboring a pronounced mesenchymal subtype driven by the key phenotypic regulator Fosl1. Indeed, orthotopic implantation of MET-expressing GBM cells corroborates their superior tumor-initiating and invasive capabilities. Thus, pericytes represent critical modulators of GBM development by orchestrating a tumor-suppressive microenvironment, highlighting the importance of their preservation in therapy.</p>}},
  author       = {{Braun, Sebastian and Bolivar, Paulina and Oudenaarden, Clara and Sjölund, Jonas and Bocci, Matteo and Harbst, Katja and Talkhoncheh, Mehrnaz Safaee and Phung, Bengt and Cordero, Eugenia and Rosberg, Rebecca and Johansson, Elinn and Jönsson, Göran B and Pietras, Alexander and Pietras, Kristian}},
  issn         = {{2041-1723}},
  keywords     = {{Pericytes/metabolism; Glioblastoma/pathology; Tumor Microenvironment/immunology; Humans; Animals; Brain Neoplasms/pathology; Mice; Cell Line, Tumor; Proto-Oncogene Proteins c-met/metabolism; Hepatocyte Growth Factor/metabolism; Paracrine Communication; Proto-Oncogene Proteins c-fos/metabolism; Tumor-Associated Macrophages/metabolism; Macrophages/metabolism}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Pericytes orchestrate a tumor-restraining microenvironment in glioblastoma}},
  url          = {{http://dx.doi.org/10.1038/s41467-025-66985-1}},
  doi          = {{10.1038/s41467-025-66985-1}},
  volume       = {{16}},
  year         = {{2025}},
}