@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 {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 {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 {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 {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 {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} }