Compressive stress drives adhesion-dependent unjamming transitions in breast cancer cell migration

Abstract

Cellular unjamming is the collective fluidization of cell motion and has been linked to many biological processes, including development, wound repair, and tumor growth. In tumor growth, the uncontrolled proliferation of cancer cells in a confined space generates mechanical compressive stress. However, because multiple cellular and molecular mechanisms may be operating simultaneously, the role of compressive stress in unjamming transitions during cancer progression remains unknown. Here, we investigate which mechanism dominates in a dense, mechanically stressed monolayer. We find that long-term mechanical compression triggers cell arrest in benign epithelial cells and enhances cancer cell migration in transitions correlated with cell shape, leading us to examine the contributions of cell–cell adhesion and substrate traction in unjamming transitions. We show that cadherin-mediated cell–cell adhesion regulates differential cellular responses to compressive stress and is an important driver of unjamming in stressed monolayers. Importantly, compressive stress does not induce the epithelial–mesenchymal transition in unjammed cells. Furthermore, traction force microscopy reveals the attenuation of traction stresses in compressed cells within the bulk monolayer regardless of cell type and motility. As traction within the bulk monolayer decreases with compressive pressure, cancer cells at the leading edge of the cell layer exhibit sustained traction under compression. Together, strengthened intercellular adhesion and attenuation of traction forces within the bulk cell sheet under compression lead to fluidization of the cell layer and may impact collective cell motion in tumor development and breast cancer progression.

Polyploid/Multinucleated Giant and Slow-Cycling Cancer Cell Enrichment in Response to X-ray Irradiation of Human Glioblastoma Multiforme Cells Differing in Radioresistance and TP53/PTEN Status

“…In this regard, our data may be contradictory to the recent data on increased E-cadherin as a strong indicator and prerequisite of compressive stress-induced UJT and increased migration rate in “scratch” tests of metastatic mouse breast cancer cell line 4T1 [ 100 ]. The authors concluded that the upregulation of E-cadherin is required for compression-induced unjamming, and that E-cadherin-dependent cell–cell adhesion is a key regulator and effector upon compression.…”

Mechanical compression regulates tumor spheroid invasion into a 3D collagen matrix

“…These changes were result of speed change, not persistence length change. While the reason for this differential response requires further investigation, the work presented here is consistent with previous work carried out on the compression of confluent 2D cell sheets [15,16]. In these studies, a wound healing assay was used to quantify the motility of cells.…”

“…Studies of roles of compression on tumor cell migration have mostly focused on single cells. In a 2D setting where cells were plated on a substrate, compression can enhance the migration and invasion of breast [15][16][17], pancreatic [18] and brain cancer cells [19]. There is limited work in a more physiologically realistic 3D setting where cells were embedded within 3D ECMs [20,21].…”

Interstitial flow potentiates TGF-β/Smad-signaling activity in lung cancer spheroids in a 3D-microfluidic chip

“…The role of IF is important due to its direct influence on the remodeling of the ECM, where compressive, tensional [11][12][13] and shear forces are sensed by cell-surface receptors that activate mechanotransduction pathways to trigger biochemical signals. 14,15 This further leads to the activation and upregulation of many core EMT cytokines, 7 including the TGF-β cytokine, known as a key EMT inducer.…”