@article {671, title = {The cancer glycocalyx mechanically primes integrin-mediated growth and survival.}, journal = {Nature}, volume = {511}, year = {2014}, month = {2014 Jul 17}, pages = {319-25}, abstract = {

Malignancy is associated with altered expression of glycans and glycoproteins that contribute to the cellular glycocalyx. We constructed a glycoprotein expression signature, which revealed that metastatic tumours upregulate expression of bulky glycoproteins. A computational model predicted that these glycoproteins would influence transmembrane receptor spatial organization and function. We tested this prediction by investigating whether bulky glycoproteins in the glycocalyx promote a tumour phenotype in human cells by increasing integrin adhesion and signalling. Our data revealed that a bulky glycocalyx facilitates integrin clustering by funnelling active integrins into adhesions and altering integrin state by applying tension to matrix-bound integrins, independent of actomyosin contractility. Expression of large tumour-associated glycoproteins in non-transformed mammary cells promoted focal adhesion assembly and facilitated integrin-dependent growth factor signalling to support cell growth and survival. Clinical studies revealed that large glycoproteins are abundantly expressed on circulating tumour cells from patients with advanced disease. Thus, a bulky glycocalyx is a feature of tumour cells that could foster metastasis by mechanically enhancing cell-surface receptor function.

}, keywords = {Animals, Breast, Cell Line, Tumor, Cell Proliferation, Cell Survival, Fibroblasts, Glycocalyx, Glycoproteins, Humans, Immobilized Proteins, Integrins, Mice, Molecular Targeted Therapy, Mucin-1, Neoplasm Metastasis, Neoplasms, Neoplastic Cells, Circulating, Protein Binding, Receptors, Cell Surface}, issn = {1476-4687}, doi = {10.1038/nature13535}, author = {Paszek, Matthew J and DuFort, Christopher C and Rossier, Olivier and Bainer, Russell and Mouw, Janna K and Godula, Kamil and Hudak, Jason E and Lakins, Jonathon N and Wijekoon, Amanda C and Cassereau, Luke and Rubashkin, Matthew G and Magbanua, Mark J and Thorn, Kurt S and Davidson, Michael W and Rugo, Hope S and Park, John W and Hammer, Daniel A and Giannone, Gr{\'e}gory and Bertozzi, Carolyn R and Weaver, Valerie M} } @article {311, title = {Actomyosin-mediated cellular tension drives increased tissue stiffness and β-catenin activation to induce epidermal hyperplasia and tumor growth.}, journal = {Cancer Cell}, volume = {19}, year = {2011}, month = {2011 Jun 14}, pages = {776-91}, abstract = {

Tumors and associated stroma manifest mechanical properties that promote cancer. Mechanosensation of tissue stiffness activates the Rho/ROCK pathway to increase actomyosin-mediated cellular tension to re-establish force equilibrium. To determine how actomyosin tension affects tissue homeostasis and tumor development, we expressed conditionally active ROCK2 in mouse skin. ROCK activation elevated tissue stiffness via increased collagen. β-catenin, a key element of mechanotranscription pathways, was stabilized by ROCK activation leading to nuclear accumulation, transcriptional activation, and consequent hyperproliferation and skin thickening. Inhibiting actomyosin contractility by blocking LIMK or myosin ATPase attenuated these responses, as did FAK inhibition. Tumor number, growth, and progression were increased by ROCK activation, while ROCK blockade was inhibitory, implicating actomyosin-mediated cellular tension and consequent collagen deposition as significant tumor promoters.

}, keywords = {Actomyosin, Animals, beta Catenin, Biomechanical Phenomena, Cell Proliferation, Cells, Cultured, Epidermis, Humans, Hyperplasia, Mice, Papilloma, rho-Associated Kinases, Signal Transduction, Skin Neoplasms}, issn = {1878-3686}, doi = {10.1016/j.ccr.2011.05.008}, author = {Samuel, Michael S and Lopez, Jose I and McGhee, Ewan J and Croft, Daniel R and Strachan, David and Timpson, Paul and Munro, June and Schr{\"o}der, Ewald and Zhou, Jing and Brunton, Valerie G and Barker, Nick and Clevers, Hans and Sansom, Owen J and Anderson, Kurt I and Weaver, Valerie M and Olson, Michael F} } @article {346, title = {Effect of substrate stiffness and PDGF on the behavior of vascular smooth muscle cells: implications for atherosclerosis.}, journal = {J Cell Physiol}, volume = {225}, year = {2010}, month = {2010 Oct}, pages = {115-22}, abstract = {

Vascular disease, such as atherosclerosis, is accompanied by changes in the mechanical properties of the vessel wall. Although altered mechanics is thought to contribute to disease progression, the molecular mechanisms whereby vessel wall stiffening could promote vascular occlusive disease remain unclear. It is well known that platelet-derived growth factor (PDGF) is a major stimulus for the abnormal migration and proliferation of vascular smooth muscle cells (VSMCs) and contributes critically to vascular disease. Here we used engineered substrates with tunable mechanical properties to explore the effect of tissue stiffness on PDGF signaling in VSMCs as a potential mechanism whereby vessel wall stiffening could promote vascular disease. We found that substrate stiffness significantly enhanced PDGFR activity and VSMC proliferation. After ligand binding, PDGFR followed distinct routes of activation in cells cultured on stiff versus soft substrates, as demonstrated by differences in its intensity and duration of activation, sensitivity to cholesterol extracting agent, and plasma membrane localization. Our results suggest that stiffening of the vessel wall could actively promote pathogenesis of vascular disease by enhancing PDGFR signaling to drive VSMC growth and survival.

}, keywords = {Acrylic Resins, Animals, Atherosclerosis, Cattle, Cell Culture Techniques, Cell Movement, Cell Proliferation, Cells, Cultured, Elasticity, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle, Platelet-Derived Growth Factor, Receptors, Platelet-Derived Growth Factor}, issn = {1097-4652}, doi = {10.1002/jcp.22202}, author = {Brown, Xin Q and Bartolak-Suki, Erzsebet and Williams, Corin and Walker, Mathew L and Weaver, Valerie M and Wong, Joyce Y} } @article {356, title = {SWI/SNF chromatin remodeling enzyme ATPases promote cell proliferation in normal mammary epithelial cells.}, journal = {J Cell Physiol}, volume = {223}, year = {2010}, month = {2010 Jun}, pages = {667-78}, abstract = {

The ATPase subunits of the SWI/SNF chromatin remodeling enzymes, Brahma (BRM) and Brahma-related gene 1 (BRG1), can induce cell cycle arrest in BRM and BRG1 deficient tumor cell lines, and mice heterozygous for Brg1 are pre-disposed to breast tumors, implicating loss of BRG1 as a mechanism for unregulated cell proliferation. To test the hypothesis that loss of BRG1 can contribute to breast cancer, we utilized RNA interference to reduce the amounts of BRM or BRG1 protein in the nonmalignant mammary epithelial cell line, MCF-10A. When grown in reconstituted basement membrane (rBM), these cells develop into acini that resemble the lobes of normal breast tissue. Contrary to expectations, knockdown of either BRM or BRG1 resulted in an inhibition of cell proliferation in monolayer cultures. This inhibition was strikingly enhanced in three-dimensional rBM culture, although some BRM-depleted cells were later able to resume proliferation. Cells did not arrest in any specific stage of the cell cycle; instead, the cell cycle length increased by approximately 50\%. Thus, SWI/SNF ATPases promote cell cycle progression in nonmalignant mammary epithelial cells.

}, keywords = {Adenosine Triphosphatases, Basement Membrane, Cell Cycle, Cell Line, Cell Proliferation, Chromatin Assembly and Disassembly, DNA Helicases, Doxycycline, Epithelial Cells, Female, Gene Knockdown Techniques, Humans, Mammary Glands, Human, Nuclear Proteins, Protein Subunits, RNA, Small Interfering, RNA, Small Nucleolar, Transcription Factors, Up-Regulation}, issn = {1097-4652}, doi = {10.1002/jcp.22072}, author = {Cohet, Nathalie and Stewart, Kathleen M and Mudhasani, Rajini and Asirvatham, Ananthi J and Mallappa, Chandrashekara and Imbalzano, Karen M and Weaver, Valerie M and Imbalzano, Anthony N and Nickerson, Jeffrey A} }