@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 {331, title = {The extracellular matrix at a glance.}, journal = {J Cell Sci}, volume = {123}, year = {2010}, month = {2010 Dec 15}, pages = {4195-200}, keywords = {Animals, Extracellular Matrix, Extracellular Matrix Proteins, Fibrosis, Homeostasis, Humans, Neoplasms}, issn = {1477-9137}, doi = {10.1242/jcs.023820}, author = {Frantz, Christian and Stewart, Kathleen M 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 {401, title = {Three-dimensional context regulation of metastasis.}, journal = {Clin Exp Metastasis}, volume = {26}, year = {2009}, month = {2009}, pages = {35-49}, abstract = {

Tumor progression ensues within a three-dimensional microenvironment that consists of cellular and non-cellular components. The extracellular matrix (ECM) and hypoxia are two non-cellular components that potently influence metastasis. ECM remodeling and collagen cross-linking stiffen the tissue stroma to promote transformation, tumor growth, motility and invasion, enhance cancer cell survival, enable metastatic dissemination, and facilitate the establishment of tumor cells at distant sites. Matrix degradation can additionally promote malignant progression and metastasis. Tumor hypoxia is functionally linked to altered stromal-epithelial interactions. Hypoxia additionally induces the expression of pro-migratory, survival and invasion genes, and up-regulates expression of ECM components and modifying enzymes, to enhance tumor progression and metastasis. Synergistic interactions between matrix remodeling and tumor hypoxia influence common mechanisms that maximize tumor progression and cooperate to drive metastasis. Thus, clarifying the molecular pathways by which ECM remodeling and tumor hypoxia intersect to promote tumor progression should identify novel therapeutic targets.

}, keywords = {Cell Division, Collagen, Disease Progression, Homeostasis, Humans, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplasms}, issn = {1573-7276}, doi = {10.1007/s10585-008-9209-8}, author = {Erler, Janine T and Weaver, Valerie M} } @article {421, title = {Tensional homeostasis and the malignant phenotype.}, journal = {Cancer Cell}, volume = {8}, year = {2005}, month = {2005 Sep}, pages = {241-54}, abstract = {

Tumors are stiffer than normal tissue, and tumors have altered integrins. Because integrins are mechanotransducers that regulate cell fate, we asked whether tissue stiffness could promote malignant behavior by modulating integrins. We found that tumors are rigid because they have a stiff stroma and elevated Rho-dependent cytoskeletal tension that drives focal adhesions, disrupts adherens junctions, perturbs tissue polarity, enhances growth, and hinders lumen formation. Matrix stiffness perturbs epithelial morphogenesis by clustering integrins to enhance ERK activation and increase ROCK-generated contractility and focal adhesions. Contractile, EGF-transformed epithelia with elevated ERK and Rho activity could be phenotypically reverted to tissues lacking focal adhesions if Rho-generated contractility or ERK activity was decreased. Thus, ERK and Rho constitute part of an integrated mechanoregulatory circuit linking matrix stiffness to cytoskeletal tension through integrins to regulate tissue phenotype.

}, keywords = {3T3 Cells, Animals, Cell Line, Tumor, Cell Shape, Cytoskeleton, Homeostasis, Mice, Neoplasms, Phenotype, Stress, Mechanical, Stromal Cells}, issn = {1535-6108}, doi = {10.1016/j.ccr.2005.08.010}, author = {Paszek, Matthew J and Zahir, Nastaran and Johnson, Kandice R and Lakins, Johnathon N and Rozenberg, Gabriela I and Gefen, Amit and Reinhart-King, Cynthia A and Margulies, Susan S and Dembo, Micah and Boettiger, David and Hammer, Daniel A and Weaver, Valerie M} } @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 {506, title = {The tension mounts: mechanics meets morphogenesis and malignancy.}, journal = {J Mammary Gland Biol Neoplasia}, volume = {9}, year = {2004}, month = {2004 Oct}, pages = {325-42}, abstract = {

The tissue microenvironment regulates mammary gland development and tissue homeostasis through soluble, insoluble and cellular cues that operate within the three dimensional architecture of the gland. Disruption of these critical cues and loss of tissue architecture characterize breast tumors. The developing and lactating mammary gland are also subject to a plethora of tensional forces that shape the morphology of the gland and orchestrate its functionally differentiated state. Moreover, malignant transformation of the breast is associated with dramatic changes in gland tension that include elevated compression forces, high tensional resistance stresses and increased extracellular matrix stiffness. Chronically increased mammary gland tension may influence tumor growth, perturb tissue morphogenesis, facilitate tumor invasion, and alter tumor survival and treatment responsiveness. Because mammary tissue differentiation is compromised by high mechanical force and transformed cells exhibit altered mechanoresponsiveness, malignant transformation of the breast may be functionally linked to perturbed tensional-homeostasis. Accordingly, it will be important to define the role of tensional force in mammary gland development and tumorigenesis. Additionally, it will be critical to identify the key molecular elements regulating tensional-homeostasis of the mammary gland and thereafter to characterize their associated mechanotransduction pathways.

}, keywords = {Animals, Biomechanical Phenomena, Cell Transformation, Neoplastic, Homeostasis, Humans, Morphogenesis, Neoplasms}, issn = {1083-3021}, doi = {10.1007/s10911-004-1404-x}, author = {Paszek, Matthew J and Weaver, Valerie M} }