@article {731, title = {Tumor mechanics and metabolic dysfunction.}, journal = {Free Radic Biol Med}, volume = {79}, year = {2015}, month = {2015 Feb}, pages = {269-80}, abstract = {

Desmosplasia is a characteristic of most solid tumors and leads to fibrosis through abnormal extracellular matrix (ECM) deposition, remodeling, and posttranslational modifications. The resulting stiff tumor stroma not only compromises vascular integrity to induce hypoxia and impede drug delivery, but also promotes aggressiveness by potentiating the activity of key growth, invasion, and survival pathways. Intriguingly, many of the protumorigenic signaling pathways that are mechanically activated by ECM stiffness also promote glucose uptake and aerobic glycolysis, and an altered metabolism is a recognized hallmark of cancer. Indeed, emerging evidence suggests that metabolic alterations and an abnormal ECM may cooperatively drive cancer cell aggression and treatment resistance. Accordingly, improved methods to monitor tissue mechanics and metabolism promise to improve diagnostics and treatments to ameliorate ECM stiffening and elevated mechanosignaling may improve patient outcome. Here we discuss the interplay between ECM mechanics and metabolism in tumor biology and suggest that monitoring these processes and targeting their regulatory pathways may improve diagnostics, therapy, and the prevention of malignant transformation.

}, issn = {1873-4596}, doi = {10.1016/j.freeradbiomed.2014.11.020}, author = {Tung, Jason C and Barnes, J Matthew and Desai, Shraddha R and Sistrunk, Christopher and Conklin, Matthew W and Schedin, Pepper and Eliceiri, Kevin W and Keely, Patricia J and Seewaldt, Victoria L and Weaver, Valerie M} } @article {226, title = {Tissue mechanics modulate microRNA-dependent PTEN expression to regulate malignant progression.}, journal = {Nat Med}, year = {2014}, month = {2014 Mar 16}, abstract = {

Tissue mechanics regulate development and homeostasis and are consistently modified in tumor progression. Nevertheless, the fundamental molecular mechanisms through which altered mechanics regulate tissue behavior and the clinical relevance of these changes remain unclear. We demonstrate that increased matrix stiffness modulates microRNA expression to drive tumor progression through integrin activation of β-catenin and MYC. Specifically, in human and mouse tissue, increased matrix stiffness induced miR-18a to reduce levels of the tumor suppressor phosphatase and tensin homolog (PTEN), both directly and indirectly by decreasing levels of homeobox A9 (HOXA9). Clinically, extracellular matrix stiffness correlated directly and significantly with miR-18a expression in human breast tumor biopsies. miR-18a expression was highest in basal-like breast cancers in which PTEN and HOXA9 levels were lowest, and high miR-18a expression predicted poor prognosis in patients with luminal breast cancers. Our findings identify a mechanically regulated microRNA circuit that can promote malignancy and suggest potential prognostic roles for HOXA9 and miR-18a levels in stratifying patients with luminal breast cancers.

}, issn = {1546-170X}, doi = {10.1038/nm.3497}, author = {Mouw, Janna K and Yui, Yoshihiro and Damiano, Laura and Bainer, Russell O and Lakins, Johnathon N and Acerbi, Irene and Ou, Guanqing and Wijekoon, Amanda C and Levental, Kandice R and Gilbert, Penney M and Hwang, E Shelley and Chen, Yunn-Yi and Weaver, Valerie M} } @article {321, title = {Tumor microenvironment and progression.}, journal = {J Surg Oncol}, volume = {103}, year = {2011}, month = {2011 May 1}, pages = {468-74}, abstract = {

Tumor blood vessels are heterogeneous, of at least six distinct types, are induced primarily by vascular endothelial growth factor-A (VEGF-A), and provide a potentially useful therapeutic target. Breast cancer is characterized by changes in the microenvironment that result in altered tensional homeostasis. Also, breast cancers arise as the result of epigenetic as well as genetic changes. Tumor blood vessel pericytes result, in part, from bone marrow precursor cells, and VEGF is a negative regulator of glioblastoma tumor cell invasion.

}, keywords = {Angiogenesis Inhibitors, Breast Neoplasms, Disease Progression, Female, Humans, Molecular Targeted Therapy, Neoplasm Invasiveness, Neoplasms, Neovascularization, Pathologic, Tumor Microenvironment, Vascular Endothelial Growth Factor A}, issn = {1096-9098}, doi = {10.1002/jso.21709}, author = {Dvorak, Harold F and Weaver, Valerie M and Tlsty, Thea D and Bergers, Gabriele} } @article {386, title = {A tense situation: forcing tumour progression.}, journal = {Nat Rev Cancer}, volume = {9}, year = {2009}, month = {2009 Feb}, pages = {108-22}, abstract = {

Cells within tissues are continuously exposed to physical forces including hydrostatic pressure, shear stress, and compression and tension forces. Cells dynamically adapt to force by modifying their behaviour and remodelling their microenvironment. They also sense these forces through mechanoreceptors and respond by exerting reciprocal actomyosin- and cytoskeletal-dependent cell-generated force by a process termed \&$\#$39;mechanoreciprocity\&$\#$39;. Loss of mechanoreciprocity has been shown to promote the progression of disease, including cancer. Moreover, the mechanical properties of a tissue contribute to disease progression, compromise treatment and might also alter cancer risk. Thus, the changing force that cells experience needs to be considered when trying to understand the complex nature of tumorigenesis.

}, keywords = {Animals, Cell Transformation, Neoplastic, Cytoskeleton, Disease Progression, Gene Expression, Humans, Mechanotransduction, Cellular, Neoplasms, Neoplastic Processes, Stress, Mechanical}, issn = {1474-1768}, doi = {10.1038/nrc2544}, author = {Butcher, Darci T and Alliston, Tamara and Weaver, Valerie M} } @article {401, title = {Three-dimensional context regulation of metastasis.}, journal = {Clin Exp Metastasis}, volume = {26}, year = {2009}, month = {2009}, pages = {35-49}, abstract = {

Tumor progression ensues within a three-dimensional microenvironment that consists of cellular and non-cellular components. The extracellular matrix (ECM) and hypoxia are two non-cellular components that potently influence metastasis. ECM remodeling and collagen cross-linking stiffen the tissue stroma to promote transformation, tumor growth, motility and invasion, enhance cancer cell survival, enable metastatic dissemination, and facilitate the establishment of tumor cells at distant sites. Matrix degradation can additionally promote malignant progression and metastasis. Tumor hypoxia is functionally linked to altered stromal-epithelial interactions. Hypoxia additionally induces the expression of pro-migratory, survival and invasion genes, and up-regulates expression of ECM components and modifying enzymes, to enhance tumor progression and metastasis. Synergistic interactions between matrix remodeling and tumor hypoxia influence common mechanisms that maximize tumor progression and cooperate to drive metastasis. Thus, clarifying the molecular pathways by which ECM remodeling and tumor hypoxia intersect to promote tumor progression should identify novel therapeutic targets.

}, keywords = {Cell Division, Collagen, Disease Progression, Homeostasis, Humans, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplasms}, issn = {1573-7276}, doi = {10.1007/s10585-008-9209-8}, author = {Erler, Janine T and Weaver, Valerie M} } @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 {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} } @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} }