SNAIL‐induced epithelial‐to‐mesenchymal transition produces concerted biophysical changes from altered cytoskeletal gene expression

Abstract

A growing body of evidence suggests that the developmental process of epithelial-to-mesenchymal transition (EMT) is co-opted by cancer cells to metastasize to distant sites. This transition is associated with morphologic elongation and loss of cell-cell adhesions, though little is known about how it alters cell biophysical properties critical for migration. Here, we use multiple-particle tracking (MPT) microrheology and traction force cytometry to probe how genetic induction of EMT in epithelial MCF7 breast cancer cells changes their intracellular stiffness and extracellular force exertion, respectively, relative to an empty vector control. This analysis demonstrated that EMT alone was sufficient to produce dramatic cytoskeletal softening coupled with increases in cell-exerted traction forces. Microarray analysis revealed that these changes corresponded with down-regulation of genes associated with actin cross-linking and up-regulation of genes associated with actomyosin contraction. Finally, we show that this loss of structural integrity to expedite migration could inhibit mesenchymal cell proliferation in a secondary tumor as it accumulates solid stress. This work demonstrates that not only does EMT enable escape from the primary tumor through loss of cell adhesions but it also induces a concerted series of biophysical changes enabling enhanced migration of cancer cells after detachment from the primary tumor.

Pterostilbene inhibits triple-negative breast cancer metastasis via inducing microRNA-205 expression and negatively modulates epithelial-to-mesenchymal transition

“…Recent studies have shown that the expression of matrix metalloproteinase (MMP) mRNAs and proteins associates tightly with diverse developmental and pathological processes, such as tumor metastasis and mammary gland involution. Snail is a transcription factor that is known to transcriptionally target MMPs during the process of EMT [25]. In the present study, pterostilbene inhibited the transcription factors ZEB1, Snail, Twist and Slug.…”

Osmotic Regulation Is Required for Cancer Cell Survival under Solid Stress

“…A series of studies have demonstrated that actin, microtubules, and intermediate filaments all contribute to support external compressive stresses (4)(5)(6). In accord with these studies, in a genetically engineered model of the epithelialmesenchymal transition, we recently found that mesenchymal cells could support less stress than their epithelial counterparts, which correlated with decreased polymerized actin and cytoplasmic stiffness (7). Here, we show that compressive stress is not actively supported by cytoskeletal filaments, but induces NHE1-dependent sodium efflux from the tumor cells.…”

Biomarkers for EMT and MET in breast cancer: An update

“…Snail-induced EMT produces concerted biophysical changes due to altered cytoskeletal gene expression. Biophysical changes associated with cancer metastasis, including elevated traction forces and loss of cytoskeletal and nuclear structure, are directly induced by EMT in the absence of any extraneous environmental cues (53). Snail promotes EMT in breast cancer cells in part via activation of nuclear ERK2 (54).…”