@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 {276, title = {Molecular profiling of prostatic acinar morphogenesis identifies PDCD4 and KLF6 as tissue architecture-specific prognostic markers in prostate cancer.}, journal = {Am J Pathol}, volume = {182}, year = {2013}, month = {2013 Feb}, pages = {363-74}, abstract = {

Histopathological classification of human prostate cancer (PCA) relies on the morphological assessment of tissue specimens but has limited prognostic value. To address this deficiency, we performed comparative transcriptome analysis of human prostatic acini generated in a three-dimensional basement membrane that recapitulates the differentiated morphological characteristics and gene expression profile of a human prostate glandular epithelial tissue. We then applied an acinar morphogenesis-specific gene profile to two independent cohorts of patients with PCA (total n = 79) and found that those with tumors expressing this profile, which we designated acini-like tumors, had a significantly lower risk of postoperative relapse compared with those tumors with a lower correlation (hazard ratio, 0.078; log-rank test P = 0.009). Multivariate analyses showed superior prognostic prediction performance using this classification system compared with clinical criteria and Gleason scores. We prioritized the genes in this profile and identified programmed cell death protein 4 (PDCD4) and Kruppel-like factor 6 (KLF6) as critical regulators and surrogate markers of prostatic tissue architectures, which form a gene signature that robustly predicts clinical prognosis with a remarkable accuracy in several large series of PCA tumors (total n = 161; concordance index, 0.913 to 0.951). Thus, by exploiting the genomic program associated with prostate glandular differentiation, we identified acini-like PCA and related molecular markers that significantly enhance prognostic prediction of human PCA.

}, keywords = {Acinar Cells, Aged, Apoptosis Regulatory Proteins, Cell Differentiation, Epithelial Cells, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Kruppel-Like Transcription Factors, Male, Middle Aged, Morphogenesis, Organ Specificity, Prognosis, Prostate, Prostatic Neoplasms, Proto-Oncogene Proteins, Recurrence, RNA-Binding Proteins, Tumor Markers, Biological}, issn = {1525-2191}, doi = {10.1016/j.ajpath.2012.10.024}, author = {Li, Chi-Rong and Su, Jimmy J-M and Wang, Wei-Yu and Lee, Michael T-L and Wang, Ting-Yun and Jiang, Kuan-Ying and Li, Chein-Feng and Hsu, Jong-Ming and Chen, Chi-Kuan and Chen, Marcelo and Jiang, Shih-Sheng and Weaver, Valerie M and Tsai, Kelvin K-C} } @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 {286, title = {Morphogenesis: Laying down the tracks.}, journal = {Nat Mater}, volume = {11}, year = {2012}, month = {2012 Jun}, pages = {490-2}, keywords = {Cell Movement, Collagen, Epithelium, Extracellular Matrix, Feedback, Morphogenesis}, issn = {1476-1122}, doi = {10.1038/nmat3345}, author = {Cassereau, Luke and DuFort, Christopher C and Weaver, Valerie M} } @article {366, title = {Matrix crosslinking forces tumor progression by enhancing integrin signaling.}, journal = {Cell}, volume = {139}, year = {2009}, month = {2009 Nov 25}, pages = {891-906}, abstract = {

Tumors are characterized by extracellular matrix (ECM) remodeling and stiffening. The importance of ECM remodeling to cancer is appreciated; the relevance of stiffening is less clear. We found that breast tumorigenesis is accompanied by collagen crosslinking, ECM stiffening, and increased focal adhesions. Induction of collagen crosslinking stiffened the ECM, promoted focal adhesions, enhanced PI3 kinase (PI3K) activity, and induced the invasion of an oncogene-initiated epithelium. Inhibition of integrin signaling repressed the invasion of a premalignant epithelium into a stiffened, crosslinked ECM and forced integrin clustering promoted focal adhesions, enhanced PI3K signaling, and induced the invasion of a premalignant epithelium. Consistently, reduction of lysyl oxidase-mediated collagen crosslinking prevented MMTV-Neu-induced fibrosis, decreased focal adhesions and PI3K activity, impeded malignancy, and lowered tumor incidence. These data show how collagen crosslinking can modulate tissue fibrosis and stiffness to force focal adhesions, growth factor signaling and breast malignancy.

}, keywords = {Aging, Animals, Breast Neoplasms, Collagen, Epidermal Growth Factor, Extracellular Matrix, Female, Fibrosis, Genes, ras, Humans, Integrins, Mammary Glands, Human, Mice, Mice, Inbred BALB C, Protein-Lysine 6-Oxidase, Signal Transduction}, issn = {1097-4172}, doi = {10.1016/j.cell.2009.10.027}, author = {Levental, Kandice R and Yu, Hongmei and Kass, Laura and Lakins, Johnathon N and Egeblad, Mikala and Erler, Janine T and Fong, Sheri F T and Csiszar, Katalin and Giaccia, Amato and Weninger, Wolfgang and Yamauchi, Mitsuo and Gasser, David L and Weaver, Valerie M} } @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 {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 {431, title = {Mammary epithelial cell: influence of extracellular matrix composition and organization during development and tumorigenesis.}, journal = {Int J Biochem Cell Biol}, volume = {39}, year = {2007}, month = {2007}, pages = {1987-94}, abstract = {

Stromal-epithelial interactions regulate mammary gland development and are critical for the maintenance of tissue homeostasis. The extracellular matrix, which is a proteinaceous component of the stroma, regulates mammary epithelial growth, survival, migration and differentiation through a repertoire of transmembrane receptors, of which integrins are the best characterized. Integrins modulate cell fate by reciprocally transducing biochemical and biophysical cues between the cell and the extracellular matrix, facilitating processes such as embryonic branching morphogenesis and lactation in the mammary gland. During breast development and cancer progression, the extracellular matrix is dynamically altered such that its composition, turnover, processing and orientation change dramatically. These modifications influence mammary epithelial cell shape, and modulate growth factor and hormonal responses to regulate processes including branching morphogenesis and alveolar differentiation. Malignant transformation of the breast is also associated with significant matrix remodeling and a progressive stiffening of the stroma that can enhance mammary epithelial cell growth, perturb breast tissue organization, and promote cell invasion and survival. In this review, we discuss the role of stromal-epithelial interactions in normal and malignant mammary epithelial cell behavior. We specifically focus on how dynamic modulation of the biochemical and biophysical properties of the extracellular matrix elicit a dialogue with the mammary epithelium through transmembrane integrin receptors to influence tissue morphogenesis, homeostasis and malignant transformation.

}, keywords = {Animals, Cell Lineage, Cell Transformation, Neoplastic, Epithelial Cells, Extracellular Matrix, Female, Humans, Mammary Glands, Human, Neoplasms}, issn = {1357-2725}, doi = {10.1016/j.biocel.2007.06.025}, author = {Kass, Laura and Erler, Janine T and Dembo, Micah 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} }