RESEARCH ARTICLE Transient external force induces phenotypic reversion of malignant epithelial structures via nitric oxide signaling Benjamin L Ricca1†, Gautham Venugopalan1†, Saori Furuta2, Kandice Tanner2,3‡, Walter A Orellana2,3, Clay D Reber1, Douglas G Brownfield1,2§, Mina J Bissell2*, Daniel A Fletcher1,2* 1Bioengineering Department and Biophysics Program, University of California, Berkeley, Berkeley, United States; 2Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, United States; 3Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, United States *For correspondence:
[email protected] (MJB);
[email protected] (DAF) Abstract Non-malignant breast epithelial cells cultured in three-dimensional laminin-rich extracellular matrix (lrECM) form well organized, growth-arrested acini, whereas malignant cells † These authors contributed form continuously growing disorganized structures. While the mechanical properties of the equally to this work microenvironment have been shown to contribute to formation of tissue-specific architecture, how Present address: ‡Laboratory of transient external force influences this behavior remains largely unexplored. Here, we show that Cell Biology, Center for Cancer brief transient compression applied to single malignant breast cells in lrECM stimulated them to Research, National Cancer form acinar-like structures, a phenomenon we term ‘mechanical reversion.’ This is analogous to Institute, Bethesda, United previously