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Lookup NU author(s): Dr Ute JungwirthORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2021, The Author(s). Profiling studies have revealed considerable phenotypic heterogeneity in cancer-associated fibroblasts (CAFs) present within the tumour microenvironment, however, functional characterisation of different CAF subsets is hampered by the lack of specific markers defining these populations. Here we show that genetic deletion of the Endo180 (MRC2) receptor, predominantly expressed by a population of matrix-remodelling CAFs, profoundly limits tumour growth and metastasis; effects that can be recapitulated in 3D co-culture assays. This impairment results from a CAF-intrinsic contractility defect and reduced CAF viability, which coupled with the lack of phenotype in the normal mouse, demonstrates that upregulated Endo180 expression by a specific, potentially targetable CAF subset is required to generate a supportive tumour microenvironment. Further, characterisation of a tumour subline selected via serial in vivo passage for its ability to overcome these stromal defects provides important insight into, how tumour cells adapt to a non-activated stroma in the early stages of metastatic colonisation.
Author(s): Jungwirth U, van Weverwijk A, Evans RJ, Jenkins L, Vicente D, Alexander J, Gao Q, Haider S, Iravani M, Isacke CM
Publication type: Article
Publication status: Published
Journal: Nature Communications
Year: 2021
Volume: 12
Issue: 1
Online publication date: 10/06/2021
Acceptance date: 26/04/2021
Date deposited: 13/02/2024
ISSN (electronic): 2041-1723
Publisher: Springer Nature
URL: https://doi.org/10.1038/s41467-021-23583-1
DOI: 10.1038/s41467-021-23583-1
Data Access Statement: The RNA-Seq data for this study (Fig. 8) have been deposited in the European Nucleotide Archive (ENA) at EMBL-EBI under accession number PRJEB36901. The whole exome sequencing data (Supplementary Fig. 8c–e) is available under the accession number PRJEB43908. Publicly available data can be accessed as follows: Series matrix files for TCGA 522 primary breast cancer samples (Fig. 1g) were downloaded from [https://tcga-data.nci.nih.gov/docs/publications/brca_2012/]. NKI data (Fig. 1g) were retrieved from breastCancerNKI R package (http://bioconductor.org/packages/release/data/experiment/html/breastCancerNKI.html). The following datasets were retrieved from the Gene Expression Omnibus (GEO) site: GSE12622 (Fig. 1c): GSE41678 Fig. 1e); GSE37614 (Fig. 1f); GSE111229 (Fig. 1h) GSE39397 (GPL13158) (Supplementary Fig. 1c). scRNASeq melanoma data (Supplementary Fig. 1d, e) (https://www.ebi.ac.uk/gxa/sc/experiments/E-EHCA-2/downloads) visualised with https://melanoma.cellgeni.sanger.ac.uk/
PubMed id: 34112782
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