Loss of miR-203 regulates cell shape and matrix adhesion through ROBO1/Rac/FAK in response to stiffness
Year: 2016
Type: article
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.
Source: The Journal of Cell Biology
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
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: bronze
Funders: National Science Foundation, U.S. Department of Defense, California Institute for Regenerative Medicine, University of California, University of California, Santa Cruz, National Institutes of Health, University of Illinois at Urbana-Champaign, Office of the President, University of California, National Cancer Institute, National Institute of General Medical Sciences
Awards: University of California, Santa Cruz IMSD Program, G1131473483, G1416682573, G1644190816, G1812895229, G2172073287, G2201867625, G3441302142, G3592001316, G3769828043, G4119534169, G4954897780, UCSC Shared Stem Cell Facility, A BIOPHYSICAL PERSPECTIVE OF BREAST CANCER METASTASIS AND TREATMENT RESISTANCE, Mechanisms Of Cell Migration On 3D Aligned Matrices, G5850682332, Graduate Research Fellowship Program, Regulation of mammary branching morphogenesis by Slit/Robo1 signaling, G8403142670, UC Santa Cruz IBSC Facility, Tension-Stat3-miR-mediated metastasis, G8632625050, G8760780107, G8853755036, HOXA9, THE EXTRACELLULAR MATRIX AND BREAST CANCER METASTASIS, G9000014631, G9000044226, G9000264566
OpenAlex ID: W2301901887