Cell-cell and cell-matrix signaling and communication between adhesion sites involve mechanisms which are required for cellular functions during normal development and homeostasis; however these cellular functions and...Cell-cell and cell-matrix signaling and communication between adhesion sites involve mechanisms which are required for cellular functions during normal development and homeostasis; however these cellular functions and mechanisms are often deregulated in cancer. Aberrant signaling at cell-cell and cell-matrix adhesion sites often involves downstream mediators including Rho GTPases and tyrosine kinases. This review discusses these molecules as putative mediators of cellular crosstalk between cell-cell and cell-matrix adhesion sites, in addition to their attractiveness as therapeutic targets in cancer. Interestingly, inter-junctional crosstalk mechanisms are frequently typified by the way in which bacterial and viral pathogens opportunistically infect or intoxicate mammalian cells. This review therefore also discusses the concept of learning from pathogen-host interaction studies to better understand coordinated communication between cell-cell and cell-matrix adhesion sites, in addition to highlighting the potential therapeutic usefulness of exploiting pathogens or their products to tap into inter-junctional crosstalk. Taken together, we feel that increased knowledge around mechanisms of cell-cell and cell-matrix adhesion site crosstalk and consequently a greater understanding of their therapeutic targeting offers a unique opportunity to contribute to the emerging molecular revolution in cancer biology.展开更多
Objective: To explore the effect of cytosolic phospholipase A2α(cPLA2α) on hepatocellular carcinoma(HCC) cell adhesion and the underlying mechanisms.Methods: Cell adhesion, detachment, and hanging-drop assays were u...Objective: To explore the effect of cytosolic phospholipase A2α(cPLA2α) on hepatocellular carcinoma(HCC) cell adhesion and the underlying mechanisms.Methods: Cell adhesion, detachment, and hanging-drop assays were utilized to examine the effect of cPLA2α on the cell-matrix and cell-cell adhesion. Downstream substrates and effectors of cPLA2α were screened via a phospho-antibody microarray.Associated signaling pathways were identified by the functional annotation tool DAVID. Candidate proteins were verified using Western blot and colocalization was investigated via immunofluorescence. Western blot and immunohistochemistry were used to detect protein expression in HCC tissues. Prognosis evaluation was conducted using Kaplan-Meier and Cox-proportional hazards regression analyses.Results: Our findings showed that cPLA2α knockdown decreases cell-matrix adhesion but increases cell-cell adhesion in HepG2 cells. Microarray analysis revealed that phosphorylation of multiple proteins at specific sites were regulated by cPLA2α. These phosphorylated proteins were involved in various biological processes. In addition, our results indicated that the focal adhesion pathway was highly enriched in the cPLA2α-relevant signaling pathway. Furthermore, cPLA2α was found to elevate phosphorylation levels of FAK and paxillin, two crucial components of focal adhesion. Moreover, localization of p-FAK to focal adhesions in the plasma membrane was significantly reduced with the downregulation of cPLA2α. Clinically, cPLA2α expression was positively correlated with p-FAK levels. Additionally, high expression of both cPLA2α and p-FAK predicted the worst prognoses for HCC patients.Conclusions: Our study indicated that cPLA2α may promote cell-matrix adhesion via the FAK/paxillin pathway, which partly explains the malignant cPLA2α phenotype seen in HCC.展开更多
We propose a mathematical model to suggest a unified explanation behind the observation that some cell types tend to spread more efficiently on stiff substrates and are able to adapt their internal stiffness to the ex...We propose a mathematical model to suggest a unified explanation behind the observation that some cell types tend to spread more efficiently on stiff substrates and are able to adapt their internal stiffness to the external stiffness. Our model also offers an explanation regarding the dependence of cell spreading on cell type. We show that our model for stiffness adaptation is in good agreement with experimental data. We also apply our model to calculate the energy of traction on bulk substrates as well as thin coatings, thereby extracting estimates of critical coating thickness as a function of cell type and coating bulk modulus.展开更多
To gain more understanding of cell-matrix adhesion,we consider an idealized theoretical model of a cluster of integrin-fibronectin bonds at the cell-matrix interface subjected to a dynamic ramping.The distributions of...To gain more understanding of cell-matrix adhesion,we consider an idealized theoretical model of a cluster of integrin-fibronectin bonds at the cell-matrix interface subjected to a dynamic ramping.The distributions of bond traction and interfacial deformation are assumed to obey classical elastic equations,whereas the dissociation/association of individual bonds as well as unfolding/refolding of fibronectin domains are described by stochastic equations.Through stochastic-elasticity coupling,we perform Monte Carlo simulations to investigate how the collective behavior and adhesion performance of the integrin-fibronectin-mediated interface are influenced by two characteristics newly incorporated in the modeling,i.e.,catchlike dissociation between integrin and fibronectin,and unfolding of repeated domains in fibronectin.The probable unfolding of fibronectin domains is found to have profound effects on the resultant adhesion energy of the integrin-fibronectin-mediated interface,and governs the failure model transiting between uniform decay and catastrophic crack-like rupture.展开更多
基金Supported by Past and present funding in the senior author’s laboratory as follows--Health Research Board of Ireland(HRA--POR-2014-545HRA/2009/49+6 种基金RP/2006/95,to Hopkins AM)Science Foundation Ireland(13/IA/19942008/RFP/NSC14272008/RFP/NSC1427 TIDA Feasibility 10,to Hopkins AM)Cancer Research Ireland,Breast Cancer IrelandBrazil Science Without Borders(CAPES-13306-13-8)the Beaumont Hospital Cancer Research and Development Trust
文摘Cell-cell and cell-matrix signaling and communication between adhesion sites involve mechanisms which are required for cellular functions during normal development and homeostasis; however these cellular functions and mechanisms are often deregulated in cancer. Aberrant signaling at cell-cell and cell-matrix adhesion sites often involves downstream mediators including Rho GTPases and tyrosine kinases. This review discusses these molecules as putative mediators of cellular crosstalk between cell-cell and cell-matrix adhesion sites, in addition to their attractiveness as therapeutic targets in cancer. Interestingly, inter-junctional crosstalk mechanisms are frequently typified by the way in which bacterial and viral pathogens opportunistically infect or intoxicate mammalian cells. This review therefore also discusses the concept of learning from pathogen-host interaction studies to better understand coordinated communication between cell-cell and cell-matrix adhesion sites, in addition to highlighting the potential therapeutic usefulness of exploiting pathogens or their products to tap into inter-junctional crosstalk. Taken together, we feel that increased knowledge around mechanisms of cell-cell and cell-matrix adhesion site crosstalk and consequently a greater understanding of their therapeutic targeting offers a unique opportunity to contribute to the emerging molecular revolution in cancer biology.
基金supported by grants from Key Project of Tianjin Natural Science Foundation (Grant No.18JCZDJC35200)NSFC-FRQS program (Grant No.81661128009)+1 种基金The Science & Technology Development Fund of Tianjin Education Commission for Higher Education (Grant No.2017KJ202)Scientific Research Foundation for Returned Scholars and Doctoral Program of Tianjin Medical University Cancer Institute and Hospital (Grant No.B1703)
文摘Objective: To explore the effect of cytosolic phospholipase A2α(cPLA2α) on hepatocellular carcinoma(HCC) cell adhesion and the underlying mechanisms.Methods: Cell adhesion, detachment, and hanging-drop assays were utilized to examine the effect of cPLA2α on the cell-matrix and cell-cell adhesion. Downstream substrates and effectors of cPLA2α were screened via a phospho-antibody microarray.Associated signaling pathways were identified by the functional annotation tool DAVID. Candidate proteins were verified using Western blot and colocalization was investigated via immunofluorescence. Western blot and immunohistochemistry were used to detect protein expression in HCC tissues. Prognosis evaluation was conducted using Kaplan-Meier and Cox-proportional hazards regression analyses.Results: Our findings showed that cPLA2α knockdown decreases cell-matrix adhesion but increases cell-cell adhesion in HepG2 cells. Microarray analysis revealed that phosphorylation of multiple proteins at specific sites were regulated by cPLA2α. These phosphorylated proteins were involved in various biological processes. In addition, our results indicated that the focal adhesion pathway was highly enriched in the cPLA2α-relevant signaling pathway. Furthermore, cPLA2α was found to elevate phosphorylation levels of FAK and paxillin, two crucial components of focal adhesion. Moreover, localization of p-FAK to focal adhesions in the plasma membrane was significantly reduced with the downregulation of cPLA2α. Clinically, cPLA2α expression was positively correlated with p-FAK levels. Additionally, high expression of both cPLA2α and p-FAK predicted the worst prognoses for HCC patients.Conclusions: Our study indicated that cPLA2α may promote cell-matrix adhesion via the FAK/paxillin pathway, which partly explains the malignant cPLA2α phenotype seen in HCC.
文摘We propose a mathematical model to suggest a unified explanation behind the observation that some cell types tend to spread more efficiently on stiff substrates and are able to adapt their internal stiffness to the external stiffness. Our model also offers an explanation regarding the dependence of cell spreading on cell type. We show that our model for stiffness adaptation is in good agreement with experimental data. We also apply our model to calculate the energy of traction on bulk substrates as well as thin coatings, thereby extracting estimates of critical coating thickness as a function of cell type and coating bulk modulus.
基金Supported by National Natural Science Foundation of China(No.31271516,No.21207084)Research Fund for Doctoral Program of Higher Education of China(No.20111401110011)China Postdoctoral Science Foundation(No.2012M521178)~~
基金This work was supported by the National Natural Science Foundation of China(Grants 11672268 and 91748209)the Fundamental Research Funds for Central Universities of China(Grant 2020XZZX005-02).
文摘To gain more understanding of cell-matrix adhesion,we consider an idealized theoretical model of a cluster of integrin-fibronectin bonds at the cell-matrix interface subjected to a dynamic ramping.The distributions of bond traction and interfacial deformation are assumed to obey classical elastic equations,whereas the dissociation/association of individual bonds as well as unfolding/refolding of fibronectin domains are described by stochastic equations.Through stochastic-elasticity coupling,we perform Monte Carlo simulations to investigate how the collective behavior and adhesion performance of the integrin-fibronectin-mediated interface are influenced by two characteristics newly incorporated in the modeling,i.e.,catchlike dissociation between integrin and fibronectin,and unfolding of repeated domains in fibronectin.The probable unfolding of fibronectin domains is found to have profound effects on the resultant adhesion energy of the integrin-fibronectin-mediated interface,and governs the failure model transiting between uniform decay and catastrophic crack-like rupture.
