Integrin-mediated traction force enhances paxillin molecular associations and adhesion dynamics that increase the invasiveness of tumor cells into a three-dimensional extracellular matrix

Published on Jun 1, 2017in Molecular Biology of the Cell4.138
路 DOI :10.1091/MBC.E16-09-0654
Armen H. Mekhdjian8
Estimated H-index: 8
(Stanford University),
FuiBoon Kai11
Estimated H-index: 11
(UCSF: University of California, San Francisco)
+ 18 AuthorsValerie M. Weaver88
Estimated H-index: 88
(UCSF: University of California, San Francisco)
Metastasis requires tumor cells to navigate through a stiff stroma and squeeze through confined microenvironments. Whether tumors exploit unique biophysical properties to metastasize remains unclear. Data show that invading mammary tumor cells, when cultured in a stiffened three-dimensional extracellular matrix that recapitulates the primary tumor stroma, adopt a basal-like phenotype. Metastatic tumor cells and basal-like tumor cells exert higher integrin-mediated traction forces at the bulk and molecular levels, consistent with a motor-clutch model in which motors and clutches are both increased. Basal-like nonmalignant mammary epithelial cells also display an altered integrin adhesion molecular organization at the nanoscale and recruit a suite of paxillin-associated proteins implicated in invasion and metastasis. Phosphorylation of paxillin by Src family kinases, which regulates adhesion turnover, is similarly enhanced in the metastatic and basal-like tumor cells, fostered by a stiff matrix, and critical for tumor cell invasion in our assays. Bioinformatics reveals an unappreciated relationship between Src kinases, paxillin, and survival of breast cancer patients. Thus adoption of the basal-like adhesion phenotype may favor the recruitment of molecules that facilitate tumor metastasis to integrin-based adhesions. Analysis of the physical properties of tumor cells and integrin adhesion composition in biopsies may be predictive of patient outcome.
馃摉 Papers frequently viewed together
#1Alice C. Chang (Stanford University)H-Index: 6
#2Armen H. Mekhdjian (Stanford University)H-Index: 8
Last. Alexander R. Dunn (Cardiovascular Institute of the South)H-Index: 37
view all 6 authors...
Integrins mediate cell adhesion to the extracellular matrix and enable the construction of complex, multicellular organisms, yet fundamental aspects of integrin-based adhesion remain poorly understood. Notably, the magnitude of the mechanical load experienced by individual integrins within living cells is unclear, due principally to limitations inherent to existing techniques. Here we use Forster resonance energy transfer-based molecular tension sensors to directly measure the distribution of lo...
Mechanical force modulates development, influences tissue homeostasis, and contributes to disease. Forces sculpt tissue-level behaviors and direct cell fate by engaging mechanoreceptors and by altering organization of the cytoskeleton and actomyosin contractility to stimulate mechanotransduction mechanisms that alter transcription. Nevertheless, how force specifically leverages mechanotransduction pathways to control transcriptional regulation of cell fate remains unclear. Here we review recent ...
#1Mei-Fong Pang (Princeton University)H-Index: 11
#2Michael J. Siedlik (Princeton University)H-Index: 6
Last. Celeste M. Nelson (Princeton University)H-Index: 57
view all 6 authors...
Breast tumors are stiffer and more hypoxic than nonmalignant breast tissue. Here we report that stiff and hypoxic microenvironments promote the development of breast cancer stem-like cells (CSC) through modulation of the integrin-linked kinase ILK. Depleting ILK blocked stiffness and hypoxia-dependent acquisition of CSC marker expression and behavior, whereas ectopic expression of ILK stimulated CSC development under softer or normoxic conditions. Stiff microenvironments also promoted tumor form...
#1FuiBoon Kai (UCSF: University of California, San Francisco)H-Index: 11
#2Hanane Laklai (UCSF: University of California, San Francisco)H-Index: 10
Last. Valerie M. WeaverH-Index: 88
view all 3 authors...
Atherosclerosis, cancer, and various chronic fibrotic conditions are characterized by an increase in the migratory behavior of resident cells and the enhanced invasion of assorted exogenous cells across a stiffened extracellular matrix (ECM). This stiffened scaffold aberrantly engages cellular mechanosignaling networks in cells, which promotes the assembly of invadosomes and lamellae for cell invasion and migration. Accordingly, deciphering the conserved molecular mechanisms whereby matrix stiff...
#1Jing-Ming Dong (Agency for Science, Technology and Research)H-Index: 1
#2Felicia P. L. Tay (Agency for Science, Technology and Research)H-Index: 11
Last. Edward Manser (Agency for Science, Technology and Research)H-Index: 58
view all 7 authors...
Focal adhesions are protein complexes that link metazoan cells to the extracellular matrix through the integrin family of transmembrane proteins. Integrins recruit many proteins to these complexes, referred to as the 鈥渁dhesome.鈥 We used proximity-dependent biotinylation (BioID) in U2OS osteosarcoma cells to label proteins within 15 to 25 nm of paxillin, a cytoplasmic focal adhesion protein, and kindlin-2, which directly binds 尾 integrins. Using mass spectrometry analysis of the biotinylated prot...
#1Hanane Laklai (UCSF: University of California, San Francisco)H-Index: 10
#2Yekaterina A. Miroshnikova (UCSF: University of California, San Francisco)H-Index: 7
Last. Valerie M. Weaver (UCSF: University of California, San Francisco)H-Index: 88
view all 22 authors...
Impaired TGF-尾 signaling due to SMAD4 mutation in PDAC tumors initiates a STAT3-dependent signaling cascade that leads to increased stromal stiffening and disease progression.
#2Roger Oria (University of Barcelona)H-Index: 9
Last. Pere Roca-Cusachs (University of Barcelona)H-Index: 37
view all 9 authors...
Integrins and talin are parts of a 鈥榤olecular clutch鈥 that mechanically links the actin cytoskeleton to the extracellular matrix. Elosegui-Artola et al. now reveal a tunable rigidity threshold, above which talin unfolds to mediate force transduction.
#1Celine Denais (Cornell University)H-Index: 7
#2Rachel M. Gilbert (Cornell University)H-Index: 1
Last. Jan Lammerding (Cornell University)H-Index: 52
view all 10 authors...
During cancer metastasis, tumor cells penetrate tissues through tight interstitial spaces, which requires extensive deformation of the cell and its nucleus. Here, we investigated mammalian tumor cell migration in confining microenvironments in vitro and in vivo. Nuclear deformation caused localized loss of nuclear envelope (NE) integrity, which led to the uncontrolled exchange of nucleo-cytoplasmic content, herniation of chromatin across the NE, and DNA damage. The incidence of NE rupture increa...
#1Mohit Kumar Jolly (Rice University)H-Index: 43
Last. Herbert Levine (Rice University)H-Index: 90
view all 10 authors...
// Mohit Kumar Jolly 1,2 , Satyendra C. Tripathi 8,* , Dongya Jia 1,5,* , Steven M. Mooney 7 , Muge Celiktas 8 , Samir M. Hanash 8,10 , Sendurai A. Mani 9,11 , Kenneth J. Pienta 12 , Eshel Ben-Jacob 1,5,6,** and Herbert Levine 1,2,3,4 1 Center for Theoretical Biological Physics, Rice University, Houston, TX, USA 2 Department of Bioengineering, Rice University, Houston, TX, USA 3 Department of Physics and Astronomy, Rice University, Houston, TX, USA 4 Department of Biosciences, Rice University, H...
#1Kevin J. CheungH-Index: 10
#2Veena Padmanaban (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 7
Last. Andrew J. Ewald (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 42
view all 11 authors...
Recent genomic studies challenge the conventional model that each metastasis must arise from a single tumor cell and instead reveal that metastases can be composed of multiple genetically distinct clones. These intriguing observations raise the question: How do polyclonal metastases emerge from the primary tumor? In this study, we used multicolor lineage tracing to demonstrate that polyclonal seeding by cell clusters is a frequent mechanism in a common mouse model of breast cancer, accounting fo...
Cited By70
#1Chia-Yu Chang (NTU: National Taiwan University)
#2Zhi-Xuan Dai (NTU: National Taiwan University)
Last. Po-Jen Shih (NTU: National Taiwan University)
view all 3 authors...
To study cell behavior, we developed a cell model to simulate cell movements and the interacting forces among cells and between cells and obstacles. The developed model simulates several cells simultaneously and examines correlations among characteristic parameters between cells and substrates during migration. We modified Odde's model to develop fundamental model, applied Gillespie's stochastic algorithm to design time during in the migration simulation, and employed Keren's membrane theory to ...
#1Manasvini Ammanamanchi (UTD: University of Texas at Dallas)H-Index: 1
#2Melanie Maurer (Cornell University)H-Index: 1
Last. Heather N. Hayenga (UTD: University of Texas at Dallas)H-Index: 13
view all 3 authors...
Macrophage to foam cell transition and their accumulation in the arterial intima are the key events that trigger atherosclerosis, a multifactorial inflammatory disease. Previous studies have linked arterial stiffness and cardiovascular disease and have highlighted the use of arterial stiffness as a potential early-stage marker. Yet the relationship between arterial stiffness and atherosclerosis in terms of macrophage function is poorly understood. Thus, it is pertinent to understand the mechanob...
#1Albertus Viljoen (UCL: Universit茅 catholique de Louvain)H-Index: 18
#2Marion Matheli茅-Guinlet (UCL: Universit茅 catholique de Louvain)H-Index: 9
Last. Yves F. Dufr锚ne (UCL: Universit茅 catholique de Louvain)H-Index: 91
view all 9 authors...
Physical forces and mechanical properties have critical roles in cellular function, physiology and disease. Over the past decade, atomic force microscopy (AFM) techniques have enabled substantial advances in our understanding of the tight relationship between force, mechanics and function in living cells and contributed to the growth of mechanobiology. In this Primer, we provide a comprehensive overview of the use of AFM-based force spectroscopy (AFM-FS) to study the strength and dynamics of cel...
#1Arseniy E. Yuzhalin (University of Texas MD Anderson Cancer Center)H-Index: 22
Interaction of a tumor with its microenvironment is an emerging field of investigation, and the crosstalk between cancer cells and the extracellular matrix is of particular interest, since cancer patients with abundant and stiff extracellular matrices display a poorer prognosis. At the post-juvenile stage, the extracellular matrix plays predominantly a structural role by providing support to cells and tissues; however, during development, matrix proteins exert a plethora of diverse signals to gu...
#1Emily Bell (Cornell University)H-Index: 21
#2Pragya Shah (Cornell University)H-Index: 6
Last. Linda VahdatH-Index: 1
view all 14 authors...
Abstract null Aberrations in nuclear size and shape are commonly used to identify cancerous tissue. However, it remains unclear whether the disturbed nuclear structure directly contributes to the cancer pathology or is merely a consequence of other events occurring during tumorigenesis. Here, we show that highly invasive and proliferative breast cancer cells have lower expression of the nuclear envelope proteins lamin A/C, leading to increased nuclear deformability that permits enhanced cell mig...
#1Mary-Kate Hayward (UCSF: University of California, San Francisco)H-Index: 3
#2Jonathon M. Muncie (Gladstone Institutes)H-Index: 7
Last. Valerie M. Weaver (UCSF: University of California, San Francisco)H-Index: 88
view all 3 authors...
Cells in tissues experience a plethora of forces that regulate their fate and modulate development and homeostasis. Cells sense mechanical cues through localized mechanoreceptors or by influencing cytoskeletal or plasma membrane organization. Cells translate force and modulate their behavior through a process termed mechanotransduction. Cells tune their tension upon exposure to chronic force by engaging cellular machinery that modulates actin tension, which in turn stimulates matrix remodeling a...
#1Arja Ray (UCSF: University of California, San Francisco)H-Index: 5
#2Paolo P. Provenzano (UMN: University of Minnesota)H-Index: 32
Organized extracellular matrix (ECM), in the form of aligned architectures, is a critical mediator of directed cancer cell migration by contact guidance, leading to metastasis in solid tumors. Current models suggest anisotropic force generation through the engagement of key adhesion and cytoskeletal complexes drives contact-guided migration. Likewise, disrupting the balance between cell-cell and cell-ECM forces, driven by ECM engagement for cells at the tumor-stromal interface, initiates and dri...
#1Cassie Liu (UNMC: University of Nebraska Medical Center)
#2Carter J. Barger (UNMC: University of Nebraska Medical Center)H-Index: 10
Last. Adam R. Karpf (UNMC: University of Nebraska Medical Center)H-Index: 46
view all 3 authors...
Forkhead box M1 (FOXM1) is a member of the conserved forkhead box (FOX) transcription factor family. Over the last two decades, FOXM1 has emerged as a multifunctional oncoprotein and a robust biomarker of poor prognosis in many human malignancies. In this review article, we address the current knowledge regarding the mechanisms of regulation and oncogenic functions of FOXM1, particularly in the context of ovarian cancer. FOXM1 and its associated oncogenic transcriptional signature are enriched i...
#1Dimitra Vasilaki (A.U.Th.: Aristotle University of Thessaloniki)H-Index: 1
#2Athina Bakopoulou (A.U.Th.: Aristotle University of Thessaloniki)H-Index: 20
Last. Konstantinos Michalakis (University of Oxford)H-Index: 1
view all 5 authors...
During metastasis, tumor cells need to adapt to their dynamic microenvironment and modify their mechanical properties in response to both chemical and mechanical stimulation. Physical interactions occur between cancer cells and the surrounding matrix including cell movements and cell shape alterations through the process of mechanotransduction. The latter describes the translation of external mechanical cues into intracellular biochemical signaling. Reorganization of both the cytoskeleton and th...
#1Barbara Zbiral (BOKU: University of Natural Resources and Life Sciences, Vienna)H-Index: 2
#2Andreas Weber (BOKU: University of Natural Resources and Life Sciences, Vienna)H-Index: 4
Last. Jos茅 L. Toca-Herrera (BOKU: University of Natural Resources and Life Sciences, Vienna)H-Index: 29
view all 5 authors...
Excessive estrogen exposure is connected with increased risk of breast cancer and has been shown to promote epithelial-mesenchymal-transition. Malignant cancer cells accumulate changes in cell mechanical and biochemical properties, often leading to cell softening. In this work we have employed atomic force microscopy to probe the influence of estrogen on the viscoelastic properties of MCF-7 breast cancer cells cultured either in normal or hormone free-medium. Estrogen led to a significant soften...
This website uses cookies.
We use cookies to improve your online experience. By continuing to use our website we assume you agree to the placement of these cookies.
To learn more, you can find in our Privacy Policy.