Loss of miR-203 regulates cell shape and matrix adhesion through ROBO1/Rac/FAK in response to stiffness |
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Authors: | Lily Thao-Nhi Le Oscar Cazares Janna K. Mouw Sharmila Chatterjee Hector Macias Angel Moran Jillian Ramos Patricia J. Keely Valerie M. Weaver Lindsay Hinck |
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Affiliation: | 1.Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064;2.Department of Cellular and Regenerative Biology, University of Wisconsin–Madison, Madison, WI 53706;3.Department of Surgery and Center for Bioengineering and Tissue Regeneration, University of California, San Francisco, San Francisco, CA 94143 |
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Abstract: | Breast tumor progression is accompanied by changes in the surrounding extracellular matrix (ECM) that increase stiffness of the microenvironment. Mammary epithelial cells engage regulatory pathways that permit dynamic responses to mechanical cues from the ECM. Here, we identify a SLIT2/ROBO1 signaling circuit as a key regulatory mechanism by which cells sense and respond to ECM stiffness to preserve tensional homeostasis. We observed that Robo1 ablation in the developing mammary gland compromised actin stress fiber assembly and inhibited cell contractility to perturb tissue morphogenesis, whereas SLIT2 treatment stimulated Rac and increased focal adhesion kinase activity to enhance cell tension by maintaining cell shape and matrix adhesion. Further investigation revealed that a stiff ECM increased Robo1 levels by down-regulating miR-203. Consistently, patients whose tumor expressed a low miR-203/high Robo1 expression pattern exhibited a better overall survival prognosis. These studies show that cells subjected to stiffened environments up-regulate Robo1 as a protective mechanism that maintains cell shape and facilitates ECM adherence. |
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