Dynamic extracellular matrix stiffening induces a phenotypic transformation and a migratory shift in epithelial cells

Abstract

Soft tissue tumors, including breast cancer, become stiffer throughout disease progression. This increase in stiffness has been shown to correlate to malignant phenotype and epithelial-to-mesenchymal transition (EMT) in vitro. Unlike current models, utilizing static increases in matrix stiffness, our group has previously created a system that allows for dynamic stiffening of an alginate–matrigel composite hydrogel to mirror the native dynamic process. Here, we utilize this system to evaluate the role of matrix stiffness on EMT and metastasis both in vitro and in vivo. Epithelial cells were seen to lose normal morphology and become protrusive and migratory after stiffening. This shift corresponded to a loss of epithelial markers and gain of mesenchymal markers in both the cell clusters and migrated cells. Furthermore, stiffening in a murine model reduced tumor burden and increased migratory behavior prior to tumor formation. Inhibition of FAK and PI3K in vitro abrogated the morphologic and migratory transformation of epithelial cell clusters. This work demonstrates the key role extracellular matrix stiffening has in tumor progression through integrin signaling and, in particular, its ability to drive EMT-related changes and metastasis.

FAK in Cancer: From Mechanisms to Therapeutic Strategies

“…Noteworthily, FAK inhibition blockaded stiffness-induced phenotypic transformation and migratory activity of epithelial cells derived from murine MMTV-PyMT tumors. It indicated that integrin-FAK signaling upon ECM stiffness possesses the ability to drive EMT-related transformation and metastasis [157].…”

Three-Dimensional in Vitro Models: A Promising Tool To Scale-Up Breast Cancer Research

“…Near-infrared irradiation of the hydrogel led to heat generation by the AuNRs, resulting in CaCl 2 permeation from the liposomes and stiffening of the hydrogel. Through this platform, inhibition of FAK and PI3K demonstrated the role of integrin signaling in tumor progression and their potential as targets of antitumor therapy …”

Biophysics Role and Biomimetic Culture Systems of ECM Stiffness in Cancer EMT

“…[65] The same phenomenon was also confirmed in vivo: migration from the injection site was increased with dynamic stiffening, thereby reducing the tumor load. [66] In theory, stiffness-mediated EMT was not a cellular autonomic process, but mechanosensing was indispensable. [13] Independently, ECM stiffness could induce breast cancer cell EMT through mechanical transduction.…”