@article{6f2879d4a42c45569c3562a7639e6a0c,
title = "Transient external force induces phenotypic reversion of malignant epithelial structures via nitric oxide signaling",
abstract = "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 {\textquoteleft}mechanical reversion.{\textquoteright} This is analogous to previously described phenotypic {\textquoteleft}reversion{\textquoteright} 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.",
author = "Ricca, {Benjamin L.} and Gautham Venugopalan and Saori Furuta and Kandice Tanner and Orellana, {Walter A.} and Reber, {Clay D.} and Brownfield, {Douglas G.} and Bissell, {Mina J.} and Fletcher, {Daniel A.}",
note = "Funding Information: We would like to thank the members of the Fletcher and Bissell Laboratories for their helpful comments and advice, especially WP Ng, KM Chan, MD Vahey, and A Lo. We thank Professor Sanjay Kumar{\textquoteright}s laboratory for use of their rheometer and Professor Michael Marletta for discussions on nitric oxide. The Bose Electroforce machine was part of the California Institute for Regenerative Medicine Shared Laboratory at UC Berkeley. This work was funded by fellowship from NIH/NIGMS (F32 GM101911, BLR) and by grants from NIH/NCI (PS-OC 60467763–112063-E, MJB and DAF) and NSF (CMMI-1235569, DAF). National Institute of General Medical Sciences F32 GM101911 Benjamin L Ricca National Science Foundation CMMI-1235569 Daniel A Fletcher National Cancer Institute PS-OC 60467763-112063-E Mina J Bissell Daniel A Fletcher The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Funding Information: 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 Funding Information: We would like to thank the members of the Fletcher and Bissell Laboratories for their helpful comments and advice, especially WP Ng, KM Chan, MD Vahey, and A Lo. We thank Professor Sanjay Kumar{\textquoteright}s laboratory for use of their rheometer and Professor Michael Marletta for discussions on nitric oxide. The Bose Electroforce machine was part of the California Institute for Regenerative Medicine Shared Laboratory at UC Berkeley. This work was funded by fellowship from NIH/NIGMS (F32 GM101911, BLR) and by grants from NIH/NCI (PS-OC 60467763–112063-E, MJB and DAF) and NSF (CMMI-1235569, DAF). Publisher Copyright: {\textcopyright} 2018, eLife Sciences Publications Ltd. All rights reserved.",
year = "2018",
month = mar,
day = "21",
doi = "10.7554/eLife.26161",
language = "English (US)",
volume = "7",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",
}