UC San Diego

Mechanical forces are recently recognized as potent regulatory signals of cellular behavior in a wide range of biological contexts, including tumor progression and stem cell differentiation (Calvo et al., 2013; Dupont et al., 2011; Engler et al., 2006; Jaalouk and Lammerding, 2009; Leight et al., 2012; Levental et al., 2009; Paszek et al., 2005). Matrix stiffness is controlled by deposition and modification of extracellular matrix, especially collagen (Provenzano et al., 2006; Provenzano et al., 2008). In breast tumors, the presence of fibrotic foci, i.e. dense clusters of collagen fibrils, is a marker of increased matrix stiffness and correlates with disease progression and poor survival (Colpaert et al., 2001; Hasebe et al., 2002). This correlation is consistent with the use of manual palpation to detect breast tumors, as the lesions are much harder than the surrounding normal tissue. These observations raise the question of how mechanical inputs from the tumor microenvironment are transduced into transcriptional outputs to drive tumor progression. Herein, I show that the transcription factor Twist1 is an essential mechano-mediator that promotes epithelial- mesenchymal transition (EMT) in response to increasing matrix stiffness. High matrix stiffness promotes nuclear translocation of Twist1 by releasing Twist1 from its cytoplasmic binding partner, G3BP2. Loss of G3BP2 leads to constitutive Twist1 nuclear localization and synergizes with increasing matrix stiffness to induce EMT and invasion. In human breast tumors, increasing matrix stiffness and reduced expression of G3BP2 predict poor survival. These findings reveal a Twist1-G3BP2 mechanotransduction pathway that responds to biomechanical signals from the tumor microenvironment to drive EMT during tumor progression