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

Benjamin L. Ricca, Gautham Venugopalan, Saori Furuta, Kandice Tanner, Walter A. Orellana, Clay D. Reber, Douglas G. Brownfield, Mina J. Bissell, Daniel A. Fletcher

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article numbere26161
StatePublished - Mar 21 2018

ASJC Scopus subject areas

  • General Neuroscience
  • General Immunology and Microbiology
  • General Biochemistry, Genetics and Molecular Biology


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