@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 {236, title = {Deconstructing Signaling in 3 Dimensions.}, journal = {Biochemistry}, year = {2014}, month = {2014 Mar 20}, abstract = {

Cells in vivo exist within the context of a multicellular tissue, where their behavior is governed by homo- and heterotypic cell-cell interactions, the material properties of the extracellular matrix, and the distribution and accessibility of various soluble and physical factors. Yet, most of the methods currently used to study and manipulate cellular behavior in vitro sacrifice physiological relevance for experimental expediency. The fallacy of such approaches to biological investigation has been highlighted by the recent development and application of three dimensional culture models to cell biology, which have revealed striking phenotypic differences in cell survival, migration, and differentiation in otherwise seemingly identical cells simply by varying culture conditions. These perplexing findings beg the question: what constitutes a three dimensional culture and why do cells behave so differently in a two versus a three dimensional culture format? In the following review, we dissect the fundamental differences between two and three dimensional culture conditions. We begin by establishing a basic definition of what \"three dimensions\" means at different biological scales and discuss how dimensionality influences cell signaling across different length scales. We identify which three dimensional features most potently influence intracellular signaling and distinguish between conserved biological principles that are maintained across culture conditions and cellular behaviors that are sensitive to microenvironmental context. Finally, we highlight state of the art molecular tools amenable to the study of signaling in three dimensions under conditions that facilitate deconstructing cell signaling in a more physiologically relevant manner.

}, issn = {1520-4995}, doi = {10.1021/bi401710d}, author = {Rubashkin, Matthew G and Ou, Guanqing 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 {661, title = {Multicellular architecture of malignant breast epithelia influences mechanics.}, journal = {PLoS One}, volume = {9}, year = {2014}, month = {2014}, pages = {e101955}, abstract = {

Cell-matrix and cell-cell mechanosensing are important in many cellular processes, particularly for epithelial cells. A crucial question, which remains unexplored, is how the mechanical microenvironment is altered as a result of changes to multicellular tissue structure during cancer progression. In this study, we investigated the influence of the multicellular tissue architecture on mechanical properties of the epithelial component of the mammary acinus. Using creep compression tests on multicellular breast epithelial structures, we found that pre-malignant acini with no lumen (MCF10AT) were significantly stiffer than normal hollow acini (MCF10A) by 60\%. This difference depended on structural changes in the pre-malignant acini, as neither single cells nor normal multicellular acini tested before lumen formation exhibited these differences. To understand these differences, we simulated the deformation of the acini with different multicellular architectures and calculated their mechanical properties; our results suggest that lumen filling alone can explain the experimentally observed stiffness increase. We also simulated a single contracting cell in different multicellular architectures and found that lumen filling led to a 20\% increase in the "perceived stiffness" of a single contracting cell independent of any changes to matrix mechanics. Our results suggest that lumen filling in carcinogenesis alters the mechanical microenvironment in multicellular epithelial structures, a phenotype that may cause downstream disruptions to mechanosensing.

}, issn = {1932-6203}, doi = {10.1371/journal.pone.0101955}, author = {Venugopalan, Gautham and Camarillo, David B and Webster, Kevin D and Reber, Clay D and Sethian, James A and Weaver, Valerie M and Fletcher, Daniel A and El-Samad, Hana and Rycroft, Chris H} } @article {241, title = {Rapid disorganization of mechanically interacting systems of mammary acini.}, journal = {Proc Natl Acad Sci U S A}, volume = {111}, year = {2014}, month = {2014 Jan 14}, pages = {658-63}, abstract = {

Cells and multicellular structures can mechanically align and concentrate fibers in their ECM environment and can sense and respond to mechanical cues by differentiating, branching, or disorganizing. Here we show that mammary acini with compromised structural integrity can interconnect by forming long collagen lines. These collagen lines then coordinate and accelerate transition to an invasive phenotype. Interacting acini begin to disorganize within 12.5 \± 4.7 h in a spatially coordinated manner, whereas acini that do not interact mechanically with other acini disorganize more slowly (in 21.8 \± 4.1 h) and to a lesser extent (P \< 0.0001). When the directed mechanical connections between acini were cut with a laser, the acini reverted to a slowly disorganizing phenotype. When acini were fully mechanically isolated from other acini and also from the bulk gel by box-cuts with a side length \<900 μm, transition to an invasive phenotype was blocked in 20 of 20 experiments, regardless of waiting time. Thus, pairs or groups of mammary acini can interact mechanically over long distances through the collagen matrix, and these directed mechanical interactions facilitate transition to an invasive phenotype.

}, keywords = {Acinar Cells, Breast Neoplasms, Cell Communication, Cell Line, Tumor, Cell Separation, Collagen, Escherichia coli, Female, Humans, Kaplan-Meier Estimate, Mammary Glands, Human, Microscopy, Atomic Force, Microscopy, Electron, Scanning, Microscopy, Fluorescence}, issn = {1091-6490}, doi = {10.1073/pnas.1311312110}, author = {Shi, Quanming and Ghosh, Rajarshi P and Engelke, Hanna and Rycroft, Chris H and Cassereau, Luke and Sethian, James A and Weaver, Valerie M and Liphardt, Jan T} } @article {266, title = {MT1-MMP-dependent control of skeletal stem cell commitment via a β1-integrin/YAP/TAZ signaling axis.}, journal = {Dev Cell}, volume = {25}, year = {2013}, month = {2013 May 28}, pages = {402-16}, abstract = {

In vitro, topographical and biophysical cues arising from the extracellular matrix (ECM) direct skeletal stem cell (SSC) commitment and differentiation. However, the mechanisms by which the SSC-ECM interface is regulated and the outcome of such interactions on stem cell fate in vivo remain unknown. Here we demonstrate that conditional deletion of the membrane-anchored metalloproteinase MT1-MMP (Mmp14) in mesenchymal progenitors, but not in committed osteoblasts, redirects SSC fate decisions from osteogenesis to adipo- and chondrogenesis. By effecting ECM remodeling, MT1-MMP regulates stem cell shape, thereby activating a β1-integrin/RhoGTPase signaling cascade and triggering the nuclear localization of the transcriptional coactivators YAP and TAZ, which serve to control SSC lineage commitment. These data identify a critical MT1-MMP/integrin/YAP/TAZ axis operative in the stem cell niche that oversees SSC fate determination.

}, keywords = {Adaptor Proteins, Signal Transducing, Adipogenesis, Animals, Antigens, CD29, Bone Marrow Cells, Cell Lineage, Cell Nucleus, Cell Shape, Cells, Cultured, Chondrogenesis, Extracellular Matrix, Gene Knock-In Techniques, Humans, Matrix Metalloproteinase 14, Mesenchymal Stromal Cells, Mice, Mice, Inbred C57BL, Mice, Transgenic, Osteogenesis, Phenotype, Phosphoproteins, Proteolysis, Signal Transduction, Stem Cell Niche, Transcription Factors, Transcriptional Activation}, issn = {1878-1551}, doi = {10.1016/j.devcel.2013.04.011}, author = {Tang, Yi and Rowe, R Grant and Botvinick, Elliot L and Kurup, Abhishek and Putnam, Andrew J and Seiki, Motoharu and Weaver, Valerie M and Keller, Evan T and Goldstein, Steven and Dai, Jinlu and Begun, Dana and Saunders, Thomas and Weiss, Stephen J} } @article {256, title = {Oncogenic targeting of BRM drives malignancy through C/EBPβ-dependent induction of α5 integrin.}, journal = {Oncogene}, year = {2013}, month = {2013 Jun 17}, abstract = {

Integrin expression and activity are altered in tumors, and aberrant integrin signaling promotes malignancy. However, how integrins become altered in tumors remains poorly understood. We discovered that oncogenic activation of MEK signaling induces cell growth and survival, and promotes the malignant phenotype of mammary epithelial cells (MECs) by increasing α5 integrin expression. We determined that MEK activates c-Myc to reduce the transcription of the SWI/SNF chromatin remodeling enzyme Brahma (BRM). Our studies revealed that reduced BRM expression and/or activity drives the malignant behavior of MECs by epigenetically promoting C/EBPβ expression to directly induce α5 integrin transcription. Consistently, we could show that restoring BRM levels normalized the malignant behavior of transformed MECs in culture and in vivo by preventing C/EBPβ-dependent α5 integrin transcription. Our findings identify a novel mechanism whereby oncogenic signaling promotes malignant transformation by regulating transcription of a key chromatin remodeling molecule that regulates integrin-dependent stromal-epithelial interactions.Oncogene advance online publication, 17 June 2013; doi:10.1038/onc.2013.220.

}, issn = {1476-5594}, doi = {10.1038/onc.2013.220}, author = {Damiano, L and Stewart, K M and Cohet, N and Mouw, J K and Lakins, J N and Debnath, J and Reisman, D and Nickerson, J A and Imbalzano, A N and Weaver, V M} } @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 {231, title = {Scanning angle interference microscopy reveals cell dynamics at the nanoscale.}, journal = {Nat Methods}, volume = {9}, year = {2012}, month = {2012 Aug}, pages = {825-7}, abstract = {

Emerging questions in cell biology necessitate nanoscale imaging in live cells. Here we present scanning angle interference microscopy, which is capable of localizing fluorescent objects with nanoscale precision along the optical axis in motile cellular structures. We use this approach to resolve nanotopographical features of the cell membrane and cytoskeleton as well as the temporal evolution, three-dimensional architecture and nanoscale dynamics of focal adhesion complexes.

}, keywords = {Cell Membrane, Cells, Cultured, Cytoskeleton, Epithelial Cells, Fibronectins, Focal Adhesions, Humans, Microscopy, Interference, Nanotechnology}, issn = {1548-7105}, doi = {10.1038/nmeth.2077}, author = {Paszek, Matthew J and DuFort, Christopher C and Rubashkin, Matthew G and Davidson, Michael W and Thorn, Kurt S and Liphardt, Jan T and Weaver, Valerie M} } @article {341, title = {Dynamic interplay between the collagen scaffold and tumor evolution.}, journal = {Curr Opin Cell Biol}, volume = {22}, year = {2010}, month = {2010 Oct}, pages = {697-706}, abstract = {

The extracellular matrix (ECM) is a key regulator of cell and tissue function. Traditionally, the ECM has been thought of primarily as a physical scaffold that binds cells and tissues together. However, the ECM also elicits biochemical and biophysical signaling. Controlled proteolysis and remodeling of the ECM network regulate tissue tension, generate pathways for migration, and release ECM protein fragments to direct normal developmental processes such as branching morphogenesis. Collagens are major components of the ECM of which basement membrane type IV and interstitial matrix type I are the most prevalent. Here we discuss how abnormal expression, proteolysis and structure of these collagens influence cellular functions to elicit multiple effects on tumors, including proliferation, initiation, invasion, metastasis, and therapy response.

}, keywords = {Cell Movement, Collagen, Humans, Neoplasms, Tissue Scaffolds}, issn = {1879-0410}, doi = {10.1016/j.ceb.2010.08.015}, author = {Egeblad, Mikala and Rasch, Morten G 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} } @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 {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 {526, title = {The organizing principle: microenvironmental influences in the normal and malignant breast.}, journal = {Differentiation}, volume = {70}, year = {2002}, month = {2002 Dec}, pages = {537-46}, abstract = {

The current paradigm for cancer initiation and progression rests on the groundbreaking discoveries of oncogenes and tumor suppressor genes. This framework has revealed much about the role of genetic alterations in the underlying signaling pathways central to normal cellular function and to tumor progression. However, it is clear that single gene theories or even sequential acquisition of mutations underestimate the nature of the genetic and epigenetic changes in tumors, and do not account for the observation that many cancer susceptibility genes (e.g. BRCA1, APC) show a high degree of tissue specificity in their association with neoplastic transformation. Therefore, the cellular and tissue context itself must confer additional and crucial information necessary for mutated genes to exert their influence. A considerable body of evidence now shows that cell-cell and cell-extracellular matrix (ECM) interactions are essential organizing principles that help define the nature of the tissue context, and play a crucial role in regulating homeostasis and tissue specificity. How this context determines functional integrity, and how its loss can lead to malignancy, appears to have much to do with tissue structure and polarity.

}, keywords = {Apoptosis, Breast, Breast Neoplasms, Coculture Techniques, Female, Humans, Signal Transduction}, issn = {0301-4681}, doi = {10.1046/j.1432-0436.2002.700907.x}, author = {Bissell, Mina J and Radisky, Derek C and Rizki, Aylin and Weaver, Valerie M and Petersen, Ole W} } @article {571, title = {Degradation of nuclear matrix and DNA cleavage in apoptotic thymocytes.}, journal = {J Cell Sci}, volume = {109 ( Pt 1)}, year = {1996}, month = {1996 Jan}, pages = {45-56}, abstract = {

In dexamethasone-treated thymocyte cultures an increase in nuclear proteolytic activity paralleled chromatin fragmentation and the appearance of small apoptotic cells. The elevation of nuclear proteolytic activity was accompanied by site-specific degradation of nuclear mitotic apparatus protein and lamin B, two essential components of the nuclear matrix. Nuclear mitotic apparatus protein phosphorylation and cleavage into 200 and 48 kDa fragments occurred within 30 minutes of dexamethasone treatment. Cleavage of lamin B, which generated a fragment of 46 kDa consistent with the central rod domain of the protein, was also detected after 30 minutes of exposure to the steroid hormone. The level of lamin B phosphorylation did not change as a result of the dexamethasone treatment and the lamina did not solubilize until the later stages of apoptosis. Initial DNA breaks, detected by the terminal transferase-mediated dUTP-biotin nick end labeling assay, occurred throughout the nuclei and solubilization of lamina was not required for this process to commence. The data presented in this paper support a model of apoptotic nuclear destruction brought about by the site-specific proteolysis of key structural proteins. Both the nuclear mitotic apparatus protein and lamin B were specifically targeted by protease(s) at early stages of the cell death pathway, which possibly initiate the cascade of degradative events in apoptosis.

}, keywords = {alpha 1-Antichymotrypsin, Animals, Apoptosis, Cell Nucleus, Cells, Cultured, Dexamethasone, DNA, DNA Damage, Endopeptidases, Lamin Type B, Lamins, Male, Microscopy, Electron, Nuclear Matrix, Nuclear Proteins, Rats, Rats, Sprague-Dawley, Spindle Apparatus, Thymus Gland, Time Factors}, issn = {0021-9533}, author = {Weaver, V M and Carson, C E and Walker, P R and Chaly, N and Lach, B and Raymond, Y and Brown, D L and Sikorska, M} }