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

In fibrosis and cancer, degradation of basement membrane (BM) and cell invasion are considered as key outcomes of a cellular transformation called epithelial-mesenchymal transition (EMT). Here, we pose a converse question-can preexisting physical defects in the BM matrix cause EMT in normal epithelial cells? On a BM-mimicking matrix of collagen-IV-coated polyacrylamide (PA) gel, we have discovered a reverse phenomenon in which preexisting defects trigger EMT in normal epithelial cells. Through spatiotemporal measurements and simulations in silico, we demonstrate that the EMT precedes cellular mechanoactivation on defective matrices, but they occur concurrently on stiff matrices. The defect-dependent EMT caused cell invasion though a stroma-mimicking collagen-I layer, which could be disabled through MMP9 inhibition. Our findings reveal that the known BM degradation caused by cellular EMT and invasion is not a one-way process. Instead, normal epithelial cells can exploit physical defects in the BM matrix to undergo disease-like cellular transformations.