@article {736, title = {Fighting the force: Potential of homeobox genes for tumor microenvironment regulation.}, journal = {Biochim Biophys Acta}, volume = {1855}, year = {2015}, month = {2015 Apr}, pages = {248-253}, abstract = {

Tumor cells exist in a constantly evolving stromal microenvironment composed of vasculature, immune cells and cancer-associated fibroblasts, all residing within a dynamic extracellular matrix. In this review, we examine the biochemical and biophysical interactions between these various stromal cells and their matrix microenvironment. While the stroma can alter tumor progression via multiple mechanisms, we emphasize the role of homeobox genes in detecting and modulating the mechanical changes in the microenvironment during tumor progression.

}, issn = {0006-3002}, doi = {10.1016/j.bbcan.2015.03.004}, author = {Northcott, Josette M and Northey, Jason J and Barnes, J Matthew and Weaver, Valerie M} } @article {641, title = {Force engages vinculin and promotes tumor progression by enhancing PI3K activation of phosphatidylinositol (3,4,5)-triphosphate.}, journal = {Cancer Res}, volume = {74}, year = {2014}, month = {2014 Sep 1}, pages = {4597-611}, abstract = {

Extracellular matrix (ECM) stiffness induces focal adhesion assembly to drive malignant transformation and tumor metastasis. Nevertheless, how force alters focal adhesions to promote tumor progression remains unclear. Here, we explored the role of the focal adhesion protein vinculin, a force-activated mechanotransducer, in mammary epithelial tissue transformation and invasion. We found that ECM stiffness stabilizes the assembly of a vinculin-talin-actin scaffolding complex that facilitates PI3K-mediated phosphatidylinositol (3,4,5)-triphosphate phosphorylation. Using defined two- and three-dimensional matrices, a mouse model of mammary tumorigenesis with vinculin mutants, and a novel super resolution imaging approach, we established that ECM stiffness, per se, promotes the malignant progression of a mammary epithelium by activating and stabilizing vinculin and enhancing Akt signaling at focal adhesions. Our studies also revealed that vinculin strongly colocalizes with activated Akt at the invasive border of human breast tumors, where the ECM is stiffest, and we detected elevated mechanosignaling. Thus, ECM stiffness could induce tumor progression by promoting the assembly of signaling scaffolds, a conclusion underscored by the significant association we observed between highly expressed focal adhesion plaque proteins and malignant transformation across multiple types of solid cancer. See all articles in this Cancer Research section, "Physics in Cancer Research."

}, issn = {1538-7445}, doi = {10.1158/0008-5472.CAN-13-3698}, author = {Rubashkin, Matthew G and Cassereau, Luke and Bainer, Russell and DuFort, Christopher C and Yui, Yoshihiro and Ou, Guanqing and Paszek, Matthew J and Davidson, Michael W and Chen, Yunn-Yi and Weaver, Valerie M} } @article {336, title = {Forcing form and function: biomechanical regulation of tumor evolution.}, journal = {Trends Cell Biol}, volume = {21}, year = {2011}, month = {2011 Jan}, pages = {47-56}, abstract = {

Cancer cells exist in a constantly evolving tissue microenvironment of diverse cell types within a proteinaceous extracellular matrix. As tumors evolve, the physical forces within this complex microenvironment change, with pleiotropic effects on both cell- and tissue-level behaviors. Recent work suggests that these biomechanical factors direct tissue development and modulate tissue homeostasis, and, when altered, crucially influence tumor evolution. In this review, we discuss the biomechanical regulation of cell and tissue homeostasis from the molecular, cellular and tissue levels, including how modifications of this physical dialogue could contribute to cancer etiology. Because of the broad impact of biomechanical factors on cell and tissue functions, an understanding of tumor evolution from the biomechanical perspective should improve risk assessment, clinical diagnosis and the efficacy of cancer treatment.

}, keywords = {Animals, Biomechanical Phenomena, Cell Transformation, Neoplastic, Extracellular Matrix, Humans, Neoplasms, Signal Transduction}, issn = {1879-3088}, doi = {10.1016/j.tcb.2010.08.015}, author = {Yu, Hongmei and Mouw, Janna Kay and Weaver, Valerie M} } @article {371, title = {Filamin A-beta1 integrin complex tunes epithelial cell response to matrix tension.}, journal = {Mol Biol Cell}, volume = {20}, year = {2009}, month = {2009 Jul}, pages = {3224-38}, abstract = {

The physical properties of the extracellular matrix (ECM) regulate the behavior of several cell types; yet, mechanisms by which cells recognize and respond to changes in these properties are not clear. For example, breast epithelial cells undergo ductal morphogenesis only when cultured in a compliant collagen matrix, but not when the tension of the matrix is increased by loading collagen gels or by increasing collagen density. We report that the actin-binding protein filamin A (FLNa) is necessary for cells to contract collagen gels, and pull on collagen fibrils, which leads to collagen remodeling and morphogenesis in compliant, low-density gels. In stiffer, high-density gels, cells are not able to contract and remodel the matrix, and morphogenesis does not occur. However, increased FLNa-beta1 integrin interactions rescue gel contraction and remodeling in high-density gels, resulting in branching morphogenesis. These results suggest morphogenesis can be \"tuned\" by the balance between cell-generated contractility and opposing matrix stiffness. Our findings support a role for FLNa-beta1 integrin as a mechanosensitive complex that bidirectionally senses the tension of the matrix and, in turn, regulates cellular contractility and response to this matrix tension.

}, keywords = {Animals, Antigens, CD29, Biomechanical Phenomena, Cell Line, Tumor, Collagen, Contractile Proteins, Epithelial Cells, Extracellular Matrix, Filamins, Gels, Humans, Mice, Microfilament Proteins, Morphogenesis, Myosin Light Chains, Phosphorylation, Protein Binding}, issn = {1939-4586}, doi = {10.1091/mbc.E08-12-1186}, author = {Gehler, Scott and Baldassarre, Massimiliano and Lad, Yatish and Leight, Jennifer L and Wozniak, Michele A and Riching, Kristin M and Eliceiri, Kevin W and Weaver, Valerie M and Calderwood, David A and Keely, Patricia J} }