ADAMTS3 restricts cancer invasion in models of early breast cancer progression through enhanced fibronectin degradation
Institution: Barts Cancer Institute, Queen Mary University of London
Corresponding Researcher: Richard Grose
Data Link(s): https://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD041461 ADAMTS3 tissue expression data are available on Gene Expression Profiling Interactive Analysis (GEPIA, http://gepia.cancer-pku.cn), with data generated by the TCGA research Network (https://www.cancer.gov/tcga) and the Genotype-Tissue Expression project (GTEx, https://gtexportal.org). Single cell ADAMTS3 expression data are available on the Human Protein Atlas (https://www.proteinatlas.org) and under the accession code GSE164898. DCIS organoid data is available under accession code GSE69994. Integrin expression data was extracted from previous RNAseq data located in Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/) with the accession code GSE224401. All further datasets generated and analysed in this study are available from the corresponding author upon reasonable request.
Keyword(s): proteases, ADAMTS3, luminal cells, fibronectin
Summary
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.
