Lung cancer is the leading cause of cancer-related deaths, primarily due to 
distant metastatic disease. Metastatic lung cancer cells can undergo an 
epithelial-to-mesenchymal transition (EMT) regulated by various transcription 
factors, including a double-negative feedback loop between the microRNA-200 
(miR-200) family and ZEB1, but the precise mechanisms by which ZEB1-dependent 
EMT promotes malignancy remain largely undefined. Although the cell-intrinsic 
effects of EMT are important for tumor progression, the reciprocal dynamic 
crosstalk between mesenchymal cancer cells and the extracellular matrix (ECM) is 
equally critical in regulating invasion and metastasis. Investigating the 
collaborative effect of EMT and ECM in the metastatic process reveals increased 
collagen deposition in metastatic tumor tissues as a direct consequence of 
amplified collagen gene expression in ZEB1-activated mesenchymal lung cancer 
cells. In addition, collagen fibers in metastatic lung tumors exhibit greater 
linearity and organization as a result of collagen crosslinking by the lysyl 
oxidase (LOX) family of enzymes. Expression of the LOX and LOXL2 isoforms is 
directly regulated by miR-200 and ZEB1, respectively, and their upregulation in 
metastatic tumors and mesenchymal cell lines is coordinated to that of collagen. 
Functionally, LOXL2, as opposed to LOX, is the principal isoform that crosslinks 
and stabilizes insoluble collagen deposition in tumor tissues. In turn, focal 
adhesion formation and FAK/SRC signaling is activated in mesenchymal tumor cells 
by crosslinked collagen in the ECM. Our study is the first to validate direct 
regulation of LOX and LOXL2 by the miR-200/ZEB1 axis, defines a novel mechanism 
driving tumor metastasis, delineates collagen as a prognostic marker, and 
identifies LOXL2 as a potential therapeutic target against tumor progression.