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

Ute Jungwirth, Antoinette Weverwijk, Rachel J. Evans, Liam Jenkins, David Vicente, John Alexander, Qiong Gao, Syed Haider, Marjan Iravani and Clare M. Isacke ()
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Ute Jungwirth: The Institute of Cancer Research
Antoinette Weverwijk: The Institute of Cancer Research
Rachel J. Evans: The Institute of Cancer Research
Liam Jenkins: The Institute of Cancer Research
David Vicente: The Institute of Cancer Research
John Alexander: The Institute of Cancer Research
Qiong Gao: The Institute of Cancer Research
Syed Haider: The Institute of Cancer Research
Marjan Iravani: The Institute of Cancer Research
Clare M. Isacke: The Institute of Cancer Research

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-23583-1

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