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Brain metastasis-associated fibroblasts shape the tumour microenvironment to enhance cancer cell invasion.

Overview

Authors: Barbora Výmolová1, Lucie Pfeiferová2, Tadeáš Karel Smetana1, Petr Výmola1,3, Nikola Ternerová1, Michal Zubaľ1,4, Michal Kolář2, Jana Šáchová2, Soňa Gyönyörová1, Eva Balážiová1, Magdalena Houdová Megová1, Jakub Červenka5, Helena Kupcová Skalníková5, Michal Španko6, Karel Smetana Jr.6, Lukáš Lacina6, David Netuka7, Robert Tomáš8, Petr Bušek1, Aleksi Šedo1
  1. Laboratory of Cancer Cell Biology, Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine Charles University Prague 2 Czech Republic
  2. Laboratory of Genomics and Bioinformatics Institute of Molecular Genetics of the Czech Academy of Sciences Prague 4 Czech Republic
  3. Present address: Protein Chemistry, Department of Translational Medicine, Faculty of Medicine Lund University Malmö Sweden
  4. Present address: Department of Oncology, Second Faculty of Medicine Charles University and Motol and Homolka University Hospital Prague 5 Czech Republic
  5. Laboratory of Proteomics, Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine Charles University Prague 2 Czech Republic
  6. Institute of Anatomy, First Faculty of Medicine Charles University Prague 2 Czech Republic
  7. Department of Neurosurgery and Neurooncology, First Faculty of Medicine Charles University and Military University Hospital Prague 6 Czech Republic
  8. Department of Neurosurgery Motol and Homolka University Hospital Prague 5 Czech Republic
Journal: Brain pathology (Zurich, Switzerland), article e70129
Dates: received 26 November 2025; accepted 17 July 2026; published online 4 August 2026; in print August 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1111/bpa.70129 · PMID 42551489 · PMCID PMC13437050 · OpenAlex W7172425476
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: genetics / omics (modality), human (organism), other condition (population), cellular / molecular (subfield)
Methods: Statistics, Connectivity
Keywords: brain metastases, cancer‐associated fibroblasts, cell migration, extracellular matrix, primary cell culture, transcriptome
Topic: Brain Metastases and Treatment (Pulmonary and Respiratory Medicine, Medicine), according to OpenAlex
Funding: Univerzita Karlova v Praze (GAUK 342522); Ministerstvo Zdravotnictví Ceské Republiky (NU22‐03‐00318); Ministerstvo Školství, Mládeže a Tělovýchovy (Ministry of Education, Youth and Sports) (EATRIS‐CZ LM2023053); Programme EXCELES (LX22NPO5102); Project ‘Center of Tumor Ecology’ (CZ.02.1.01/0.0/0.0/16_019/0000785); Operational Program Research, Development and Education
Citations: not cited yet (Europe PMC); 71 references in the paper

Abstract

Brain metastases (BrM) are a frequent and life‐threatening complication of solid tumours, with lung cancer representing their most common source. While cancer‐associated fibroblasts (CAFs) are well‐established contributors to tumour progression in many extracranial malignancies, their presence and function within the brain tumour microenvironment, where fibroblasts have long been considered scarce or absent, remain poorly understood. Here, we isolated and characterised fibroblast‐like cells from 13 human BrMs of diverse origins. These BrM‐associated CAFs (BrM‐CAFs) expressed canonical CAF markers and showed reduced proliferation and increased senescence compared to normal fibroblasts. Their transcriptome was enriched for extracellular matrix (ECM)‐related genes, including multiple collagens, fibronectin, and matrix‐remodelling enzymes. In vitro, BrM‐CAFs produced a fibrillar ECM, and in BrM tissues, their abundance was associated with collagen I and fibronectin deposition. Transcriptomic, proteomic, and secretome analyses further revealed that BrM‐CAFs produce multiple cytokines, chemokines, and growth factors that promote cell motility. BrM‐CAF conditioned medium promoted both monocyte migration and the migration of cancer cells, including established cell lines and patient‐derived lung cancer BrM cells; monocyte migration was partially reduced by inhibition of CCL2/CCR2 signalling, whereas blocking CXCL12, CXCL16, or CX3CL1 attenuated BrM‐CAF‐induced cancer cell migration. Beyond these effects on migration, exposure to BrM‐CAFs increased cancer cell invasion in transwell and heterotypic 3D spheroid assays. In contrast, their effects on cancer cell proliferation were limited and did not indicate a growth‐promoting role. Exposure to BrM‐CAFs was also associated with increased expression of interferon‐stimulated genes in cancer cells. Together, our findings support a role for BrM‐CAFs in shaping the brain metastatic microenvironment through ECM remodelling and the secretion of pro‐migratory mediators, promoting monocyte and cancer cell migration and enhancing cancer cell invasion. These data identify BrM‐CAFs as active stromal participants in BrM biology and support further investigation of their biological, diagnostic, and therapeutic relevance.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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Data

Data links

Data availability statement

The transcriptomic datasets used in this article are available in the ArrayExpress database (https://www.ebi.ac.uk/biostudies/arrayexpress) under the accession numbers E‐MTAB‐13242 and E‐MTAB‐15451. The proteomic datasets, including complete Spectronaut file, together with raw data, have been deposited to the ProteomeXchange Consortium via the PRoteomics IDEntifications (PRIDE) partner repository with the dataset identifier PXD080067.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, pages, dates, 20 authors, 6 keywords, 6 funders, 69 references.

Cite

This paper

Výmolová, B., Pfeiferová, L., Smetana, T. K., Výmola, P., Ternerová, N., Zubaľ, M., Kolář, M., Šáchová, J., Gyönyörová, S., Balážiová, E., Houdová Megová, M., Červenka, J., Kupcová Skalníková, H., Španko, M., Smetana, K., Lacina, L., Netuka, D., Tomáš, R., Bušek, P., & Šedo, A. (2026). Brain metastasis-associated fibroblasts shape the tumour microenvironment to enhance cancer cell invasion. Brain pathology (Zurich, Switzerland), e70129. https://doi.org/10.1111/bpa.70129

BibTeX

@article{vymolova2026brain,
author = {Výmolová, Barbora and Pfeiferová, Lucie and Smetana, Tadeáš Karel and Výmola, Petr and Ternerová, Nikola and Zubaľ, Michal and Kolář, Michal and Šáchová, Jana and Gyönyörová, Soňa and Balážiová, Eva and Houdová Megová, Magdalena and Červenka, Jakub and Kupcová Skalníková, Helena and Španko, Michal and Smetana, Karel and Lacina, Lukáš and Netuka, David and Tomáš, Robert and Bušek, Petr and Šedo, Aleksi},
title = {{Brain metastasis-associated fibroblasts shape the tumour microenvironment to enhance cancer cell invasion}},
journal = {Brain pathology (Zurich, Switzerland)},
year = {2026},
month = aug,
pages = {e70129},
publisher = {Wiley},
issn = {1015-6305},
doi = {10.1111/bpa.70129},
url = {https://doi.org/10.1111/bpa.70129},
pmid = {42551489},
pmcid = {PMC13437050}
}

RIS

TY - JOUR
AU - Výmolová, Barbora
AU - Pfeiferová, Lucie
AU - Smetana, Tadeáš Karel
AU - Výmola, Petr
AU - Ternerová, Nikola
AU - Zubaľ, Michal
AU - Kolář, Michal
AU - Šáchová, Jana
AU - Gyönyörová, Soňa
AU - Balážiová, Eva
AU - Houdová Megová, Magdalena
AU - Červenka, Jakub
AU - Kupcová Skalníková, Helena
AU - Španko, Michal
AU - Smetana, Karel
AU - Lacina, Lukáš
AU - Netuka, David
AU - Tomáš, Robert
AU - Bušek, Petr
AU - Šedo, Aleksi
TI - Brain metastasis-associated fibroblasts shape the tumour microenvironment to enhance cancer cell invasion
T2 - Brain pathology (Zurich, Switzerland)
J2 - Brain Pathol
PY - 2026
DA - 2026/08/04
SP - e70129
SN - 1015-6305
PB - Wiley
DO - 10.1111/bpa.70129
UR - https://doi.org/10.1111/bpa.70129
LA - en
ER -

CSL-JSON

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