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

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.

Systems-level network modeling deciphers the master regulators of phenotypic plasticity and heterogeneity in melanoma

“…Several parallels can be drawn between phenotypic switching in melanoma and EMT in epithelial cancers. First, the invasive phenotype has upregulation of several mesenchymal genes and EMT-regulators such as ZEB1, WNT5A, CDH2 ( Su et al., 2017 ; Vandamme et al., 2020 ), as well as that of matrix metalloproteases (MMPs) that can change the extracellular matrix (ECM) stiffness ( Arozarena and Wellbrock, 2017 ), as typically observed in EMT ( Wei et al., 2015 ; Deng et al., 2020 ). However, ZEB1 and ZEB2, both EMT-inducing factors, promote opposite phenotypes in melanoma ( Denecker et al., 2014 ).…”

“…In addition, MITF directly regulates ECM and focal adhesion pathways, which have been associated with inducing phenotypic switching ( Dilshat et al., 2021 ; Spoerri et al., 2021 ). Also, EMT-ECM bidirectional crosstalk was recently implicated in phenotypic switching ( Deng et al., 2021 ), endorsing a melanoma-ECM-EMT axis governing phenotypic heterogeneity. Other EMT regulators such as TWIST and AP-1 ( Feldker et al., 2020 ) are also reported to drive phenotypic plasticity in melanoma ( Caramel et al., 2013 ; Verfaillie et al., 2015 ).…”

Nrf2 modulates the hybrid epithelial/mesenchymal phenotype and Notch signaling during collective cancer migration

“…The complex interplay between signaling and migratory dynamics also underscores future theoretical challenges that are not explicitly considered in our current model, including (1) the coupling of biochemical and mechanical regulation of cell migration, (2) the effect of cell proliferation on cell patterning, and (3) the context-specificity of the EMT program in terms of both transcriptional response and number of intermediate phenotypes in the EMT spectrum. [57][58][59] Future experimental and computational investigations will be required to fully understand the role of Nrf2 on cancer invasion, and more physiologically relevant invasion models should be investigated to understand the impact of the Nrf2-EMT-Notch network on collective cancer invasion.…”

Lineage Plasticity in Cancer: The Tale of a Skin-Walker

“…In addition to the stromal cells, components of the extracellular matrix (ECM) can also instigate cellular plasticity [ 201 ]. Matrix stiffness can promote EMT and stemness in breast, colorectal and liver cancers [ 202 , 203 , 204 ]. Extracellular proteases can also stimulate cellular plasticity [ 201 , 205 , 206 ].…”