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Physical defects in basement membrane-mimicking collagen-IV matrices trigger cellular EMT and invasion

Abstract

Epithelial-mesenchymal transition (EMT) is a key disease phenotype of cells in fibrosis and cancer, which often leads to cellular invasion and degradation of the basement membrane (BM). Here, we pose a converse question - can preexisting physical defects in the BM matrix cause EMT in normal epithelial cells? To investigate this unknown cellular response to BM defects, we fabricated soft polyacrylamide (PA) gels, coated with collagen-IV (col-IV) and introduced a defect in the gel before culturing monolayers of MCF10A normal mammary epithelial cells. Around the defect, cells degraded col-IV and showed EMT signatures (vimentin, SNAIL, and ZEB1) within 3 days. The inhibition of matrix metalloproteinase-9 (MMP9) abrogated this defect-dependent EMT and col-IV degradation. Through spatiotemporal measurements and simulations in silico, we demonstrate that while EMT induction and stress fiber formation occur concurrently on stiff matrices, the defect-induced EMT precedes cellular mechano-activation. Next, to assess whether such EMT response could lead to cell invasion, we constructed a multi-layered matrix from collagen-I and PA gels, coated with col-IV, introduced a defect and cultured an epithelial colony. We found that the defect-dependent EMT persisted in this 3D system and caused a downward invasion of cells, which could be disabled by MMP9 inhibition. Thus, our findings reveal that the known process of BM degradation due to cellular EMT and invasion might not be a one-way process. Instead, normal epithelial cells can exploit the existing physical defects in the BM matrix, which could arise from wounds or prior matrix degradation, to induce disease-like cellular transformations.

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Publication details

The article was received on 22 Feb 2018, accepted on 11 May 2018 and first published on 16 May 2018


Article type: Paper
DOI: 10.1039/C8IB00034D
Citation: Integr. Biol., 2018, Accepted Manuscript
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    Physical defects in basement membrane-mimicking collagen-IV matrices trigger cellular EMT and invasion

    C. Walter, J. Davis, J. Mathur and A. Pathak, Integr. Biol., 2018, Accepted Manuscript , DOI: 10.1039/C8IB00034D

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