Abstract
Proteases have long been associated with cancer progression, due to their ability to facilitate invasion upon matrix remodelling. However, proteases are not simply degraders of the matrix, but also play fundamental roles in modulating cellular behaviour through the proteolytic processing of specific substrates. Indeed, proteases can elicit both pro- and anti- tumorigenic effects depending on context. Using a heterocellular spheroid model of breast cancer progression, we demonstrate the repressive function of myoepithelial ADAMTS3, with its loss directing myoepithelial-led invasion of luminal cells through a physiologically relevant matrix. Degradomic analysis, using terminal amine isotopic labelling of substrates (TAILS), combined with functional assays, implicate ADAMTS3 as a mediator of fibronectin degradation. We show further that loss of ADAMTS3 enhances levels of fibronectin in the microenvironment, promoting invasion through canonical integrin α5β1 activation. Our data highlight a tumour suppressive role for ADAMTS3 in early stage breast cancer, and contribute to the growing evidence that proteases can restrain cancer progression.
Original language | English |
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Pages (from-to) | 74-89 |
Number of pages | 16 |
Journal | Matrix biology : Journal of the International Society for Matrix Biology |
Volume | 121 |
Early online date | 17 Jun 2023 |
DOIs | |
Publication status | Published - 31 Aug 2023 |
Bibliographical note
Funding Information:We thank Dr Jennifer Gomm, Ian Goulding and the Breast Cancer Now Cell Bank for collecting and making the primary myoepithelial cells available for in this study. We would also like to acknowledge the proteomics core facility at Technical University of Denmark for their role in assisting with the generation of degradomic data. This work was supported by Cancer Research UK (C10847/A27781), Breast Cancer Now (2017NovPR988), Barts Charity (MRC0173), Rosetrees Trust (M501-F1), CRUK Microscopy Core Service Grant (C16420/A18066) and by a CRUK UK Centre Grant to Barts Cancer Institute (C355/A25137). U.K. is supported by a Novo Nordisk Foundation Young Investigator Award (NNF16OC0020670).
Funding Information:
We thank Dr Jennifer Gomm, Ian Goulding and the Breast Cancer Now Cell Bank for collecting and making the primary myoepithelial cells available for in this study. We would also like to acknowledge the proteomics core facility at Technical University of Denmark for their role in assisting with the generation of degradomic data. This work was supported by Cancer Research UK ( C10847/A27781 ), Breast Cancer Now ( 2017NovPR988 ), Barts Charity ( MRC0173 ), Rosetrees Trust ( M501-F1 ), CRUK Microscopy Core Service Grant ( C16420/A18066 ) and by a CRUK UK Centre Grant to Barts Cancer Institute ( C355/A25137 ). U.K. is supported by a Novo Nordisk Foundation Young Investigator Award ( NNF16OC0020670 ).
Keywords
- 3D models
- ADAMTS
- Breast cancer
- Fibronectin
- Invasion
- Myoepithelial cell
- Proteases
ASJC Scopus subject areas
- Molecular Biology