Transient external force induces phenotypic reversion of malignant epithelial structures via nitric oxide signaling

• Published in: eLife 2018-03, Vol.7
• Main Authors: Ricca, Benjamin L, Venugopalan, Gautham, Furuta, Saori, Tanner, Kandice, Orellana, Walter A, Reber, Clay D, Brownfield, Douglas G, Bissell, Mina J, Fletcher, Daniel A
• Format: Article
• Language: English
• Subjects: Acinar Cells - drug effects; Acinar Cells - metabolism; Biochemistry; Breast - cytology; Breast - drug effects; Breast - metabolism; Breast cancer; breast epithelial cells; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Cancer Biology; Cell Biology; Cell Line; Cell Line, Tumor; Compression; Epithelial cells; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Experiments; Extracellular matrix; Extracellular Matrix - metabolism; Genotype & phenotype; Humans; Laminin; Laminin - metabolism; Laminin - pharmacology; Malignancy; Mechanical properties; mechanobiology; Microscopy, Confocal; Morphogenesis; Nitric oxide; Nitric Oxide - metabolism; Nitrogen oxides; Phenotypic reversion; Polymerization; Reversion; Shear strain; Signal Transduction - drug effects; Stress, Mechanical; Time-Lapse Imaging - methods
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.26161

Non-malignant breast epithelial cells cultured in three-dimensional laminin-rich extracellular matrix (lrECM) form well organized, growth-arrested acini, whereas malignant cells form continuously growing disorganized structures. While the mechanical properties of the microenvironment have been shown to contribute to formation of tissue-specific architecture, how transient external force influences this behavior remains largely unexplored. Here, we show that brief transient compression applied to single malignant breast cells in lrECM stimulated them to form acinar-like structures, a phenomenon we term 'mechanical reversion.' This is analogous to previously described phenotypic 'reversion' using biochemical inhibitors of oncogenic pathways. Compression stimulated nitric oxide production by malignant cells. Inhibition of nitric oxide production blocked mechanical reversion. Compression also restored coherent rotation in malignant cells, a behavior that is essential for acinus formation. We propose that external forces applied to single malignant cells restore cell-lrECM engagement and signaling lost in malignancy, allowing them to reestablish normal-like tissue architecture.