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

Matrix Biol. 2023 Jun 17:S0945-053X(23)00074-4. doi: 10.1016/j.matbio.2023.06.005. Online ahead of print.ABSTRACTProteases 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.PMID:37336268 | DOI:10.1016/j.matbio.2023.06.005

Source: Matrix Biology - June 19, 2023 Category: Molecular Biology Authors: Shayin V Gibson Elizabeta Madzharova Amandine C Tan Michael D Allen Ulrich Auf dem Keller J Louise Jones Edward P Carter Richard P Grose Source Type: research