Abstract
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.
| Original language | English |
|---|---|
| Article number | 3516 |
| Number of pages | 17 |
| Journal | Nature Communications |
| Volume | 12 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 10 Jun 2021 |
Bibliographical note
Funding Information:This work was funded as part of Programme Funding to the Breast Cancer Now Toby Robins Research Centre (C.M.I.), Worldwide Cancer Research (15-0355, C.M.I. and U.J.) and a Schrödinger fellowship of the Austrian Science Fund (FWF) (J3434-B13, U.J.). We acknowledge NHS funding to the NIHR Biomedical Research Centre at the Royal Marsden and the ICR. We would like to thank Adam Mills for the whole exome sequencing analysis, Kristian Pietras and Jonas Sjölund for the data analysis and images in Fig. 1h, Mirjana Efremova help in accessing the data shown in Supplementary Fig. 1e, Miriam Melake for help with the matrix imaging, Gernot Walko for his imaging expertise and scientific discussions, Naomi Guppy and her team in the Breast Cancer Now Toby Robins Research Centre Nina Barough Pathology Core Facility for histopathology support, Fredrik Wallberg for help with the FACSorting and imaging, and the following facilities at the ICR; Tumour Profiling Unit, Biological Services Unit, and the FACS and Light Microscopy Facility. The results published here are in whole or part based upon data generated by the TCGA Research Network (http://cancergenome.nih.gov/).
Data availability
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)70. The following datasets were retrieved
from the Gene Expression Omnibus (GEO) site: GSE1262234 (Fig. 1c): GSE4167871
Fig. 1e); GSE3761471 (Fig. 1f); GSE1112297 (Fig. 1h) GSE39397 (GPL13158)32
(Supplementary Fig. 1c). scRNASeq melanoma data33 (Supplementary Fig. 1d, e)
(https://www.ebi.ac.uk/gxa/sc/experiments/E-EHCA-2/downloads) visualised with
https://melanoma.cellgeni.sanger.ac.uk/ and lung cancer data (Supplementary Fig. 1f)
PMID2998812936 (https://gbiomed.kuleuven.be/scRNAseq-NSCLC) visualised with
SCope (https://scope.aertslab.org/). The remaining data are available within the article,
Supplementary Information, Source Data file or available from the authors upon
request. Source data are provided with this paper.
