ADAMTS3 restricts cancer invasion in models of early breast cancer progression through enhanced fibronectin degradation

Shayin V Gibson, Elizabeta Madzharova, Amandine C Tan, Michael D Allen, Ulrich Auf dem Keller, J Louise Jones, Edward P Carter, Richard P Grose

Research output: Contribution to journalArticlepeer-review

8 Citations (SciVal)

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 languageEnglish
Pages (from-to)74-89
Number of pages16
JournalMatrix biology : Journal of the International Society for Matrix Biology
Volume121
Early online date17 Jun 2023
DOIs
Publication statusPublished - 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

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