@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 {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 {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 {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 {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} }