A Theoretical Approach to Coupling the Epithelial-Mesenchymal Transition (EMT) to Extracellular Matrix (ECM) Stiffness via LOXL2

SIMPLE SUMMARY: Epithelial-mesenchymal transition (EMT) is a key process in cancer progression through which cells weaken their cell-cell adhesion and gain mobility and invasive traits. Besides chemical signaling, recent studies have established the connection of EMT to mechanical microenvironment, such as the stiffness of extracellular matrix (ECM). LOXL2 is representative of a family of enzymes that promotes fiber cross-linking in ECM. With increased cross-linking comes increased stiffness, which induces EMT that can, in turn, elevate LOXL2 levels. As such, a positive feedback loop among EMT, LOXL2, and ECM stiffness can be formed. We built a mathematical model on a core biochemical reaction network featuring this feedback loop, and showed how strongly it drives EMT. We also illustrated mechanistically how cross-linking connects with stiffness, using a mechanical model of collagen (a major component of ECM). Using this theoretical framework, we demonstrated the heterogeneity of LOXL2/stiffness and its implications on migrating cancer cells that could seed metastasis, the growth of secondary malignant tumors. This framework can inspire experimental studies of more fine-grained mechanotransduction and biomechanical heterogeneity in cancers. ABSTRACT: The epithelial-mesenchymal transition (EMT) plays a critical role in cancer progression, being responsible in many cases for the onset of the metastatic cascade and being integral in the ability of cells to resist drug treatment. Most studies of EMT focus on its induction via chemical signals such as TGF-β or Notch ligands, but it has become increasingly clear that biomechanical features of the microenvironment such as extracellular matrix (ECM) stiffness can be equally important. Here, we introduce a coupled feedback loop connecting stiffness to the EMT transcription factor ZEB1, which acts via increasing the secretion of LOXL2 that leads to increased cross-linking of collagen fibers in the ECM. This increased cross-linking can effectively increase ECM stiffness and increase ZEB1 levels, thus setting a positive feedback loop between ZEB1 and ECM stiffness. To investigate the impact of this non-cell-autonomous effect, we introduce a computational approach capable of connecting LOXL2 concentration to increased stiffness and thereby to higher ZEB1 levels. Our results indicate that this positive feedback loop, once activated, can effectively lock the cells in a mesenchymal state. The spatial-temporal heterogeneity of the LOXL2 concentration and thus the mechanical stiffness also has direct implications for migrating cells that attempt to escape the primary tumor.