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Impairment of a distinct cancer-associated fibroblast population limits tumour growth and metastasis

Lookup NU author(s): Dr Ute JungwirthORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 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.


Publication metadata

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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Funding

Funder referenceFunder name
Breast Cancer Now Toby Robins Research Centre
NHS
Schrödinger fellowship of the Austrian Science Fund
Worldwide Cancer Research

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