@article {271, title = {A physical sciences network characterization of non-tumorigenic and metastatic cells.}, journal = {Sci Rep}, volume = {3}, year = {2013}, month = {2013}, pages = {1449}, abstract = {

To investigate the transition from non-cancerous to metastatic from a physical sciences perspective, the Physical Sciences-Oncology Centers (PS-OC) Network performed molecular and biophysical comparative studies of the non-tumorigenic MCF-10A and metastatic MDA-MB-231 breast epithelial cell lines, commonly used as models of cancer metastasis. Experiments were performed in 20 laboratories from 12 PS-OCs. Each laboratory was supplied with identical aliquots and common reagents and culture protocols. Analyses of these measurements revealed dramatic differences in their mechanics, migration, adhesion, oxygen response, and proteomic profiles. Model-based multi-omics approaches identified key differences between these cells\&$\#$39; regulatory networks involved in morphology and survival. These results provide a multifaceted description of cellular parameters of two widely used cell lines and demonstrate the value of the PS-OC Network approach for integration of diverse experimental observations to elucidate the phenotypes associated with cancer metastasis.

}, keywords = {Cell Line, Tumor, Cell Movement, Cell Size, Cell Survival, Computer Simulation, Gene Expression Regulation, Neoplastic, Humans, Models, Biological, Neoplasm Metastasis, Neoplasm Proteins, Tumor Markers, Biological}, issn = {2045-2322}, doi = {10.1038/srep01449}, author = {Agus, David B and Alexander, Jenolyn F and Arap, Wadih and Ashili, Shashanka and Aslan, Joseph E and Austin, Robert H and Backman, Vadim and Bethel, Kelly J and Bonneau, Richard and Chen, Wei-Chiang and Chen-Tanyolac, Chira and Choi, Nathan C and Curley, Steven A and Dallas, Matthew and Damania, Dhwanil and Davies, Paul C W and Decuzzi, Paolo and Dickinson, Laura and Estevez-Salmeron, Luis and Estrella, Veronica and Ferrari, Mauro and Fischbach, Claudia and Foo, Jasmine and Fraley, Stephanie I and Frantz, Christian and Fuhrmann, Alexander and Gascard, Philippe and Gatenby, Robert A and Geng, Yue and Gerecht, Sharon and Gillies, Robert J and Godin, Biana and Grady, William M and Greenfield, Alex and Hemphill, Courtney and Hempstead, Barbara L and Hielscher, Abigail and Hillis, W Daniel and Holland, Eric C and Ibrahim-Hashim, Arig and Jacks, Tyler and Johnson, Roger H and Joo, Ahyoung and Katz, Jonathan E and Kelbauskas, Laimonas and Kesselman, Carl and King, Michael R and Konstantopoulos, Konstantinos and Kraning-Rush, Casey M and Kuhn, Peter and Kung, Kevin and Kwee, Brian and Lakins, Johnathon N and Lambert, Guillaume and Liao, David and Licht, Jonathan D and Liphardt, Jan T and Liu, Liyu and Lloyd, Mark C and Lyubimova, Anna and Mallick, Parag and Marko, John and McCarty, Owen J T and Meldrum, Deirdre R and Michor, Franziska and Mumenthaler, Shannon M and Nandakumar, Vivek and O{\textquoteright}Halloran, Thomas V and Oh, Steve and Pasqualini, Renata and Paszek, Matthew J and Philips, Kevin G and Poultney, Christopher S and Rana, Kuldeepsinh and Reinhart-King, Cynthia A and Ros, Robert and Semenza, Gregg L and Senechal, Patti and Shuler, Michael L and Srinivasan, Srimeenakshi and Staunton, Jack R and Stypula, Yolanda and Subramanian, Hariharan and Tlsty, Thea D and Tormoen, Garth W and Tseng, Yiider and van Oudenaarden, Alexander and Verbridge, Scott S and Wan, Jenny C and Weaver, Valerie M and Widom, Jonathan and Will, Christine and Wirtz, Denis and Wojtkowiak, Jonathan and Wu, Pei-Hsun} } @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 {296, title = {Extracellular matrix degradation and remodeling in development and disease.}, journal = {Cold Spring Harb Perspect Biol}, volume = {3}, year = {2011}, month = {2011 Dec}, abstract = {

The extracellular matrix (ECM) serves diverse functions and is a major component of the cellular microenvironment. The ECM is a highly dynamic structure, constantly undergoing a remodeling process where ECM components are deposited, degraded, or otherwise modified. ECM dynamics are indispensible during restructuring of tissue architecture. ECM remodeling is an important mechanism whereby cell differentiation can be regulated, including processes such as the establishment and maintenance of stem cell niches, branching morphogenesis, angiogenesis, bone remodeling, and wound repair. In contrast, abnormal ECM dynamics lead to deregulated cell proliferation and invasion, failure of cell death, and loss of cell differentiation, resulting in congenital defects and pathological processes including tissue fibrosis and cancer. Understanding the mechanisms of ECM remodeling and its regulation, therefore, is essential for developing new therapeutic interventions for diseases and novel strategies for tissue engineering and regenerative medicine.

}, keywords = {Animals, Body Patterning, Cell Differentiation, Extracellular Matrix, Extracellular Matrix Proteins, Mice, Models, Biological, Neoplasms, Peptide Hydrolases, Signal Transduction, Stem Cells, Vertebrates}, issn = {1943-0264}, doi = {10.1101/cshperspect.a005058}, author = {Lu, Pengfei and Takai, Ken and Weaver, Valerie M and Werb, Zena} } @article {391, title = {Mechanics, malignancy, and metastasis: the force journey of a tumor cell.}, journal = {Cancer Metastasis Rev}, volume = {28}, year = {2009}, month = {2009 Jun}, pages = {113-27}, abstract = {

A cell undergoes many genetic and epigenetic changes as it transitions to malignancy. Malignant transformation is also accompanied by a progressive loss of tissue homeostasis and perturbations in tissue architecture that ultimately culminates in tumor cell invasion into the parenchyma and metastasis to distant organ sites. Increasingly, cancer biologists have begun to recognize that a critical component of this transformation journey involves marked alterations in the mechanical phenotype of the cell and its surrounding microenvironment. These mechanical differences include modifications in cell and tissue structure, adaptive force-induced changes in the environment, altered processing of micromechanical cues encoded in the extracellular matrix (ECM), and cell-directed remodeling of the extracellular stroma. Here, we review critical steps in this \"force journey,\" including mechanical contributions to tissue dysplasia, invasion of the ECM, and metastasis. We discuss the biophysical basis of this force journey and present recent advances in the measurement of cellular mechanical properties in vitro and in vivo. We end by describing examples of molecular mechanisms through which tumor cells sense, process and respond to mechanical forces in their environment. While our understanding of the mechanical components of tumor growth, survival and motility remains in its infancy, considerable work has already yielded valuable insight into the molecular basis of force-dependent tumor pathophysiology, which offers new directions in cancer chemotherapeutics.

}, keywords = {Animals, Biophysics, Cell Transformation, Neoplastic, Epigenesis, Genetic, Extracellular Matrix, Focal Adhesion Protein-Tyrosine Kinases, Humans, Lasers, Microscopy, Atomic Force, Models, Biological, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplasms, rho-Associated Kinases, Stress, Mechanical}, issn = {1573-7233}, doi = {10.1007/s10555-008-9173-4}, author = {Kumar, Sanjay and Weaver, Valerie M} } @article {396, title = {Biomechanical regulation of cell orientation and fate.}, journal = {Oncogene}, volume = {27}, year = {2008}, month = {2008 Nov 24}, pages = {6981-93}, abstract = {

Biomechanical regulation of tumor phenotypes have been noted for several decades, yet the function of mechanics in the co-evolution of the tumor epithelium and altered cancer extracellular matrix has not been appreciated until fairly recently. In this review, we examine the dynamic interaction between the developing epithelia and the extracellular matrix, and discuss how similar interactions are exploited by the genetically modified epithelium during tumor progression. We emphasize the process of mechanoreciprocity, which is a phenomenon observed during epithelial transformation, in which tension generated within the extracellular microenvironment induce and cooperate with opposing reactive forces within transformed epithelium to drive tumor progression and metastasis. We highlight the importance of matrix remodeling, and present a new, emerging paradigm that underscores the importance of tissue morphology as a key regulator of epithelial cell invasion and metastasis.

}, keywords = {Animals, Biochemical Processes, Bioreactors, Cell Culture Techniques, Cell Differentiation, Cell Movement, Cell Polarity, Cell Transformation, Neoplastic, Embryonic Development, Epithelial Cells, Humans, Mechanotransduction, Cellular, Models, Biological, Neoplasm Metastasis}, issn = {1476-5594}, doi = {10.1038/onc.2008.348}, author = {Lopez, J I and Mouw, J K and Weaver, V M} } @article {406, title = {Integrin-mediated signalling through the MAP-kinase pathway.}, journal = {IET Syst Biol}, volume = {2}, year = {2008}, month = {2008 Jan}, pages = {8-15}, abstract = {

The mitogen activated protein (MAP) kinase cascade, leading to extracellular-regulated kinase (ERK) activation, is a key regulator of cell growth and proliferation. The effects of ERK are mediated by differences in ERK signalling dynamics, including magnitude and duration. In vivo, ERK signalling is stimulated by both growth factors and adhesion signals. A model for adhesion-mediated ERK activation is presented. Outputs of the model such as ERK and FAK activation, as well as responses to different ligand densities, are compared with published experimental data. The model then serves as a basis for understanding how adhesion may contribute to ERK signalling through changes in the dynamics of focal adhesion kinase activation. The main parameters influencing ERK are determined through screening analyses and parameter variation. With these parameters, key points in the pathway that give rise to changes in downstream signalling dynamics are identified. In particular, oncogenic Raf and Ras promote cell growth by increasing the magnitude and duration, respectively, of ERK activity.

}, keywords = {Animals, Humans, Integrins, MAP Kinase Signaling System, Mitogen-Activated Protein Kinases, Models, Biological, ras Proteins}, issn = {1751-8849}, doi = {10.1049/iet-syb:20060058}, author = {Yee, K L and Weaver, V M and Hammer, D A} } @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 {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 {546, title = {Structural cues from the tissue microenvironment are essential determinants of the human mammary epithelial cell phenotype.}, journal = {J Mammary Gland Biol Neoplasia}, volume = {3}, year = {1998}, month = {1998 Apr}, pages = {201-13}, abstract = {

Historically, the study of normal human breast function and breast disorders has been significantly impaired by limitations inherent to available model systems. Recent improvements in human breast epithelial cell lines and three-dimensional (3-D)3 culture systems have contributed to the development of in vitro model systems that recapitulate differentiated epithelial cell phenotypes with remarkable fidelity. Molecular characterization of these human breast cell models has demonstrated that normal breast epithelial cell behavior is determined in part by the precise interplay that exists between a cell and its surrounding microenvironment. Recent functional studies of integrins in a human model system provide evidence to support the idea that the structural stability afforded by integrin-mediated cell-extracellular matrix interactions is an important determinant of normal cellular behavior, and that alterations in tissue structure can give rise to tumorigenic progression.

}, keywords = {Breast, Breast Neoplasms, Cell Line, Epithelial Cells, Extracellular Matrix, Female, Humans, Integrins, Models, Biological}, issn = {1083-3021}, author = {Schmeichel, K L and Weaver, V M and Bissell, M J} } @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} }