Loss of miR-203 regulates cell shape and matrix adhesion through ROBO1/Rac/FAK in response to stiffness
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Mar 14, 2016
- Source ID
- 10.1083/jcb.201507054
Entities
People
- Angel Moran
- Hector Macias
- Janna K Mouw
- Jillian Ramos
- Lily Thao-nhi Le
- Lindsay Hinck
- Oscar Cazares
- Patricia J. Keely
- Sharmila Chatterjee
- Valerie M Weaver
Organizations
- California Institute for Regenerative Medicine
- National Institutes of Health
- National Science Foundation
- United States Department of Defense
- University of California
- University of California, San Francisco
- University of California, Santa Cruz
- University of Wisconsin–Madison