Impairment of a distinct cancer-associated fibroblast population limits tumour growth and metastasis.
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Date
2021-06-10Author
Jungwirth, U
van Weverwijk, A
Evans, RJ
Jenkins, L
Vicente, D
Alexander, J
Gao, Q
Haider, S
Iravani, M
Isacke, CM
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Subject
Cells, Cultured
NIH 3T3 Cells
Spheroids, Cellular
Extracellular Matrix
Stromal Cells
Animals
Mice, Inbred BALB C
Mice, Knockout
Humans
Mice
Breast Neoplasms
Neoplasm Metastasis
Membrane Glycoproteins
Receptors, Cell Surface
Coculture Techniques
Tumor Stem Cell Assay
Cell Proliferation
Cell Survival
Female
Tumor Microenvironment
Cancer-Associated Fibroblasts
Research team
Molecular Cell Biology
Paediatric Solid Tumour Biology and Therapeutics
Molecular Cell Biology
Paediatric Solid Tumour Biology and Therapeutics
Language
eng
Date accepted
2021-04-26
License start date
2021-06-10
Citation
Nature communications, 2021, 12 (1), pp. 3516 - ?
Publisher
NATURE PORTFOLIO