@article {316, title = {Balancing forces: architectural control of mechanotransduction.}, journal = {Nat Rev Mol Cell Biol}, volume = {12}, year = {2011}, month = {2011 May}, pages = {308-19}, abstract = {

All cells exist within the context of a three-dimensional microenvironment in which they are exposed to mechanical and physical cues. These cues can be disrupted through perturbations to mechanotransduction, from the nanoscale-level to the tissue-level, which compromises tensional homeostasis to promote pathologies such as cardiovascular disease and cancer. The mechanisms of such perturbations suggest that a complex interplay exists between the extracellular microenvironment and cellular function. Furthermore, sustained disruptions in tensional homeostasis can be caused by alterations in the extracellular matrix, allowing it to serve as a mechanically based memory-storage device that can perpetuate a disease or restore normal tissue behaviour.

}, keywords = {Animals, Cell Adhesion, Extracellular Matrix, Homeostasis, Humans, Intercellular Junctions, Mechanotransduction, Cellular, Models, Biological, Stress, Mechanical}, issn = {1471-0080}, doi = {10.1038/nrm3112}, author = {DuFort, Christopher C and Paszek, Matthew J and Weaver, Valerie M} } @article {376, title = {Multiscale modeling of form and function.}, journal = {Science}, volume = {324}, year = {2009}, month = {2009 Apr 10}, pages = {208-12}, abstract = {

Topobiology posits that morphogenesis is driven by differential adhesive interactions among heterogeneous cell populations. This paradigm has been revised to include force-dependent molecular switches, cell and tissue tension, and reciprocal interactions with the microenvironment. It is now appreciated that tissue development is executed through conserved decision-making modules that operate on multiple length scales from the molecular and subcellular level through to the cell and tissue level and that these regulatory mechanisms specify cell and tissue fate by modifying the context of cellular signaling and gene expression. Here, we discuss the origin of these decision-making modules and illustrate how emergent properties of adhesion-directed multicellular structures sculpt the tissue, promote its functionality, and maintain its homeostasis through spatial segregation and organization of anchored proteins and secreted factors and through emergent properties of tissues, including tension fields and energy optimization.

}, keywords = {Animals, Biological Evolution, Cell Adhesion, Cell Aggregation, Cell Communication, Extracellular Matrix, Genotype, Homeostasis, Morphogenesis, Phenotype, Proteins, Signal Transduction}, issn = {1095-9203}, doi = {10.1126/science.1170107}, author = {Engler, Adam J and Humbert, Patrick O and Wehrle-Haller, Bernhard and Weaver, Valerie M} } @article {411, title = {Rac-dependent cyclin D1 gene expression regulated by cadherin- and integrin-mediated adhesion.}, journal = {J Cell Sci}, volume = {121}, year = {2008}, month = {2008 Jan 15}, pages = {226-33}, abstract = {

Integrin-mediated adhesion to substratum is required for cyclin D1 induction in mesenchymal cells, but we show here that the induction of cyclin D1 persists despite blockade of ECM-integrin signaling in MCF10A mammary epithelial cells. E-cadherin-mediated cell-cell adhesion also supports cyclin D1 induction in these cells, and the combined inhibition of both E-cadherin and integrin adhesion is required to prevent the expression of cyclin D1 mRNA and protein. Our previous studies described a pro-proliferative effect of E-cadherin in MCF10A cells, mediated by Rac, and we now show that Rac is required for cyclin D1 mRNA induction by both E-cadherin and integrin engagement. The levels of p21Cip1 and p27Kip1, Cdk inhibitors that are also targets of integrin signaling, are not affected by E-cadherin-mediated cell-cell adhesion. Finally, we show that the increased expression of cyclin D1 mRNA associated with E-cadherin-dependent cell-cell adhesion is causally linked to an increased entry into S phase. Our results identify Rac signaling to cyclin D1 as a crucial pro-proliferative effect of E-cadherin-mediated cell-cell adhesion.

}, keywords = {Cadherins, Cell Adhesion, Cell Communication, Cell Line, Tumor, Cyclin D1, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27, Gene Expression Regulation, Gene Expression Regulation, Neoplastic, Humans, Integrins, Models, Biological, rac GTP-Binding Proteins, Signal Transduction}, issn = {0021-9533}, doi = {10.1242/jcs.017012}, author = {Fournier, Alaina K and Campbell, Latoya E and Castagnino, Paola and Liu, Wendy F and Chung, Betty M and Weaver, Valerie M and Chen, Christopher S and Assoian, Richard K} } @article {511, title = {Death in the third dimension: apoptosis regulation and tissue architecture.}, journal = {Curr Opin Genet Dev}, volume = {14}, year = {2004}, month = {2004 Feb}, pages = {71-80}, abstract = {

Tissue development, homeostasis and tumor pathogenesis all depend upon a complex dialogue between multiple cell types operating within a dynamic three-dimensional (3D) tissue extracellular matrix microenvironment. A major issue is whether the spatial organization of a cell within this 3D tissue microenvironment could modulate cell responsiveness to regulate cell fate decisions such as survival, and if so how. Classic developmental model systems and transgenic animals are instructive but pose special challenges for investigators conducting signaling studies and biochemical assays in tissues. As an alternative, 3D culture model systems exist in which cell-adhesion dependent tissue architecture, heterotypic cell-cell interactions and tissue differentiation can be recapitulated with good fidelity. 3D cell culture models are slowly revealing how tissue architecture can dramatically influence how a cell responds to exogenous stimuli to modify its apoptotic behavior and hence should prove instrumental for identifying novel cell death pathways.

}, keywords = {Apoptosis, Cell Adhesion, Cell Culture Techniques, Extracellular Matrix, Gene Expression Regulation, Homeostasis, Models, Biological}, issn = {0959-437X}, doi = {10.1016/j.gde.2003.12.005}, author = {Zahir, Nastaran and Weaver, Valerie M} } @article {516, title = {Autocrine laminin-5 ligates alpha6beta4 integrin and activates RAC and NFkappaB to mediate anchorage-independent survival of mammary tumors.}, journal = {J Cell Biol}, volume = {163}, year = {2003}, month = {2003 Dec 22}, pages = {1397-407}, abstract = {

Invasive carcinomas survive and evade apoptosis despite the absence of an exogenous basement membrane. How epithelial tumors acquire anchorage independence for survival remains poorly defined. Epithelial tumors often secrete abundant amounts of the extracellular matrix protein laminin 5 (LM-5) and frequently express alpha6beta4 integrin. Here, we show that autocrine LM-5 mediates anchorage-independent survival in breast tumors through ligation of a wild-type, but not a cytoplasmic tail-truncated alpha6beta4 integrin. alpha6beta4 integrin does not mediate tumor survival through activation of ERK or AKT. Instead, the cytoplasmic tail of beta4 integrin is necessary for basal and epidermal growth factor-induced RAC activity, and RAC mediates tumor survival. Indeed, a constitutively active RAC sustains the viability of mammary tumors lacking functional beta1 and beta4 integrin through activation of NFkappaB, and overexpression of NFkappaB p65 mediates anchorage-independent survival of nonmalignant mammary epithelial cells. Therefore, epithelial tumors could survive in the absence of exogenous basement membrane through autocrine LM-5-alpha6beta4 integrin-RAC-NFkappaB signaling.

}, keywords = {Autocrine Communication, Basement Membrane, Breast Neoplasms, Carcinoma, Cell Adhesion, Cell Adhesion Molecules, Cell Line, Tumor, Cell Survival, Epidermal Growth Factor, Humans, Integrin alpha6beta4, MAP Kinase Signaling System, Neoplasm Invasiveness, NF-kappa B, Protein Structure, Tertiary, rac GTP-Binding Proteins}, issn = {0021-9525}, doi = {10.1083/jcb.200302023}, author = {Zahir, Nastaran and Lakins, Johnathon N and Russell, Alan and Ming, WenYu and Chatterjee, Chandrima and Rozenberg, Gabriela I and Marinkovich, M Peter and Weaver, Valerie M} } @article {521, title = {The tissue microenvironment as an epigenetic tumor modifier.}, journal = {Methods Mol Biol}, volume = {223}, year = {2003}, month = {2003}, pages = {315-47}, keywords = {Animals, Breast Neoplasms, Cell Adhesion, Cell Nucleus, Dimerization, Epithelial Cells, Genes, Tumor Suppressor, Humans, Keratinocytes, Models, Biological, Neoplasm Metastasis, Neoplasms, Neovascularization, Pathologic, Phenotype, Promoter Regions, Genetic, Signal Transduction, Time Factors}, issn = {1064-3745}, doi = {10.1385/1-59259-329-1:315}, author = {Unger, Meredith and Weaver, Valerie M} } @article {536, title = {Membrane-associated MMP regulators: novel cell adhesion tumor suppressor proteins?}, journal = {Dev Cell}, volume = {2}, year = {2002}, month = {2002 Jan}, pages = {6-7}, abstract = {

Matrix metalloproteinases are enzymes that regulate tissue behavior by interactions with extracellular matrix proteins. RECK, a membrane-anchored inhibitor of MMPs was recently characterized for its role in development, tissue homeostasis, and for tumor angiogenesis.

}, keywords = {Cell Adhesion, Eukaryotic Cells, Matrix Metalloproteinases, Tumor Suppressor Proteins}, issn = {1534-5807}, author = {Weaver, Valerie M} } @article {566, title = {The importance of the microenvironment in breast cancer progression: recapitulation of mammary tumorigenesis using a unique human mammary epithelial cell model and a three-dimensional culture assay.}, journal = {Biochem Cell Biol}, volume = {74}, year = {1996}, month = {1996}, pages = {833-51}, abstract = {

The extracellular matrix (ECM) is a dominant regulator of tissue development and homeostasis. \"Designer microenvironments\" in culture and in vivo model systems have shown that the ECM regulates growth, differentiation, and apoptosis in murine and human mammary epithelial cells (MEC) through a hierarchy of transcriptional events involving the intricate interplay between soluble and physical signaling pathways. Furthermore, these studies have shown that these pathways direct and in turn are influenced by the tissue structure. Tissue structure is directed by the cooperative interactions of the cell-cell and cell-ECM pathways and can be modified by stromal factors. Not surprisingly then, loss of tissue structure and alterations in ECM components are associated with the appearance and dissemination of breast tumors, and malignancy is associated with perturbations in cell adhesion, changes in adhesion molecules, and a stromal reaction. Several lines of evidence now support the contention that the pathogenesis of breast cancer is determined (at least in part) by the dynamic interplay between the ductal epithelial cells, the microenvironment, and the tissue structure (acini). Thus, to understand the mechanisms involved in carcinogenesis, the role of the microenvironment (ECM as well as the stromal cells) with respect to tissue structure should be considered and studied. Towards this goal, we have established a unique human MEC model of tumorigenesis, which in concert with a three-dimensional assay, recapitulates many of the genetic and morphological changes observed in breast in cancer in vivo. We are currently using this system to understand the role of the microenvironment and tissue structure in breast cancer progression.

}, keywords = {Animals, Breast Neoplasms, Cell Adhesion, Epithelium, Extracellular Matrix, Humans, Models, Biological, Tumor Cells, Cultured}, issn = {0829-8211}, author = {Weaver, V M and Fischer, A H and Peterson, O W and Bissell, M J} }