Migration through physical constraints is enabled by MAPK-induced cell softening via actin cytoskeleton re-organization

Abstract

Cancer cells are softer than the normal cells, and metastatic cells are even softer. These changes in biomechanical properties contribute to cancer progression by facilitating cell movement through physically constraining environments. To identify properties that enabled passage through physical constraints, cells that were more efficient at moving through narrow membrane micropores were selected from established cell lines. By examining micropore-selected human MDA MB 231 breast cancer and MDA MB 435 melanoma cancer cells, membrane fluidity and nuclear elasticity were excluded as primary contributors. Instead, reduced actin cytoskeleton anisotropy, focal adhesion density and cell stiffness were characteristics associated with efficient passage through constraints. By comparing transcriptomic profiles between the parental and selected populations, increased Ras/MAPK signalling was linked with cytoskeleton rearrangements and cell softening. MEK inhibitor treatment reversed the transcriptional, cytoskeleton, focal adhesion and elasticity changes. Conversely, expression of oncogenic KRas in parental MDA MB 231 cells, or oncogenic BRaf in parental MDA MB 435 cells, significantly reduced cell stiffness. These results reveal that MAPK signalling, in addition to tumour cell proliferation, has a significant role in regulating cell biomechanics. .

The Effects of Trifolium pratense L. Sprouts’ Phenolic Compounds on Cell Growth and Migration of MDA-MB-231, MCF-7 and HUVEC Cells

“…Chronic elevation of ROS induces intracellular oxidative damage leading to metabolic failure and cellular death [27]. Additionally, ROS act within cells to promote migration and influence the behavior of migrating cells through the reorganization of actin cytoskeleton and adhesion [28,29]. Thus, in further steps we checked red clover extracts' influences at IC 0 dosages on ROS generation.…”

“…It was mentioned previously that during cell migration, the actin cytoskeleton undergoes dynamic changes. Among the key promoting intermediators of migration are ROS, especially H 2 O 2 , which can be generated by enzymes known as nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NO X ) complexes, and molecules interacting with CAsL (MICAL) proteins [28,29]. ROS have been linked directly to reorganization of filamentous actin structures via oxidation of both cytoskeletal and nuclear actin, or cofilin-1 increasing actin polymerization.…”

Targeting Acidic Diseased Tissues by pH-Triggered Membrane-Associated Peptide Folding

“…A very different set of targeting approaches might be based on the recognition of differences in other properties of the cellular membranes in normal and diseased tissues. It has been shown that cancer cells are mechanically softer than normal cells, and that the membranes of cancer cells have increased fluidity (Sherbet, 1989;Schierbaum et al, 2017;Rudzka et al, 2019). Further, bilayer asymmetry differs between normal and cancer cells, with phosphatidyl ethanolamine appearing in larger quantities in the outer monolayer (Tan et al, 2017).…”

Bioglass could increase cell membrane fluidity with ion products to develop its bioactivity

“…Increased membrane fluidity could directly accelerate the motion of membrane protein and lipids, which facilitates the enzymatic reaction on the membrane 42 . Previous studies have shown that membrane fluidity is highly related to migration and differentiation of cells 43 . Once the cell membrane was frozen by CHS, the stimulatory effects of Si on cells migration and differentiation were totally eliminated.…”