The Experts below are selected from a list of 14382 Experts worldwide ranked by ideXlab platform
Richard Treisman - One of the best experts on this subject based on the ideXlab platform.
-
rpel family rhogaps link rac cdc42 gtp loading to g actin availability
Nature Cell Biology, 2019Co-Authors: Jessica Diring, Stephane Mouilleron, Neil Q. Mcdonald, Richard TreismanAbstract:RPEL proteins, which contain the G-actin-binding RPEL motif, coordinate cytoskeletal processes with actin dynamics. We show that the ArhGAP12- and ArhGAP32-family GTPase-activating proteins (GAPs) are RPEL proteins. We determine the structure of the ArhGAP12/G-actin complex, and show that G-actin contacts the RPEL motif and GAP domain sequences. G-actin inhibits ArhGAP12 GAP activity, and this requires the G-actin contacts identified in the structure. In B16 melanoma cells, ArhGAP12 suppresses basal Rac and Cdc42 activity, F-actin assembly, invadopodia formation and Experimental Metastasis. In this setting, ArhGAP12 mutants defective for G-actin binding exhibit more effective downregulation of Rac GTP loading following HGF stimulation and enhanced inhibition of Rac-dependent processes, including invadopodia formation. Potentiation or disruption of the G-actin/ArhGAP12 interaction, by treatment with the actin-binding drugs latrunculin B or cytochalasin D, has corresponding effects on Rac GTP loading. The interaction of G-actin with RPEL-family rhoGAPs thus provides a negative feedback loop that couples Rac activity to actin dynamics.
-
Myocardin-related transcription factors and SRF are required for cytoskeletal dynamics and Experimental Metastasis.
Nature cell biology, 2009Co-Authors: Souhila Medjkane, Cristina Perez-sanchez, Cedric Gaggioli, Erik Sahai, Richard TreismanAbstract:Rho GTPases control cytoskeletal dynamics through cytoplasmic effectors and regulate transcriptional activation through myocardin-related transcription factors (MRTFs), which are co-activators for serum response factor (SRF). We used RNA interference to investigate the contribution of the MRTF-SRF pathway to cytoskeletal dynamics in MDA-MB-231 breast carcinoma and B16F2 melanoma cells, in which basal MRTF-SRF activity is Rho-dependent. Depletion of MRTFs or SRF reduced cell adhesion, spreading, invasion and motility in culture, without affecting proliferation or inducing apoptosis. MRTF-depleted tumour cell xenografts showed reduced cell motility but proliferated normally. Tumour cells depleted of MRTF or SRF failed to colonize the lung from the bloodstream, being unable to persist after their arrival in the lung. Only a few genes show MRTF-dependent expression in both cell lines. Two of these, MYH9 (NMHCIIa) and MYL9 (MLC2), are also required for invasion and lung colonization. Conversely, expression of activated MAL/MRTF-A increases lung colonization by poorly metastatic B16F0 cells. Actin-based cell behaviour and Experimental Metastasis thus require Rho-dependent nuclear signalling through the MRTF-SRF network.
-
myocardin related transcription factors and srf are required for cytoskeletal dynamics and Experimental Metastasis
Nature Cell Biology, 2009Co-Authors: Richard Treisman, Souhila Medjkane, Cedric Gaggioli, Erik Sahai, Cristina PerezsanchezAbstract:By preventing G-actin accumulation, Rho-GTPase promotes the transcriptional activity of myocardin-related transcription factors (MRTFs), known co-factors of serum response factor (SRF). Rho-dependent MRTF expression is required for injected metastatic cell lines to colonize the lung. Rho GTPases control cytoskeletal dynamics through cytoplasmic effectors and regulate transcriptional activation through myocardin-related transcription factors (MRTFs), which are co-activators for serum response factor (SRF). We used RNA interference to investigate the contribution of the MRTF–SRF pathway to cytoskeletal dynamics in MDA-MB-231 breast carcinoma and B16F2 melanoma cells, in which basal MRTF–SRF activity is Rho-dependent. Depletion of MRTFs or SRF reduced cell adhesion, spreading, invasion and motility in culture, without affecting proliferation or inducing apoptosis. MRTF-depleted tumour cell xenografts showed reduced cell motility but proliferated normally. Tumour cells depleted of MRTF or SRF failed to colonize the lung from the bloodstream, being unable to persist after their arrival in the lung. Only a few genes show MRTF-dependent expression in both cell lines. Two of these, MYH9 (NMHCIIa) and MYL9 (MLC2), are also required for invasion and lung colonization. Conversely, expression of activated MAL/MRTF-A increases lung colonization by poorly metastatic B16F0 cells. Actin-based cell behaviour and Experimental Metastasis thus require Rho-dependent nuclear signalling through the MRTF–SRF network.
Souhila Medjkane - One of the best experts on this subject based on the ideXlab platform.
-
Myocardin-related transcription factors and SRF are required for cytoskeletal dynamics and Experimental Metastasis.
Nature cell biology, 2009Co-Authors: Souhila Medjkane, Cristina Perez-sanchez, Cedric Gaggioli, Erik Sahai, Richard TreismanAbstract:Rho GTPases control cytoskeletal dynamics through cytoplasmic effectors and regulate transcriptional activation through myocardin-related transcription factors (MRTFs), which are co-activators for serum response factor (SRF). We used RNA interference to investigate the contribution of the MRTF-SRF pathway to cytoskeletal dynamics in MDA-MB-231 breast carcinoma and B16F2 melanoma cells, in which basal MRTF-SRF activity is Rho-dependent. Depletion of MRTFs or SRF reduced cell adhesion, spreading, invasion and motility in culture, without affecting proliferation or inducing apoptosis. MRTF-depleted tumour cell xenografts showed reduced cell motility but proliferated normally. Tumour cells depleted of MRTF or SRF failed to colonize the lung from the bloodstream, being unable to persist after their arrival in the lung. Only a few genes show MRTF-dependent expression in both cell lines. Two of these, MYH9 (NMHCIIa) and MYL9 (MLC2), are also required for invasion and lung colonization. Conversely, expression of activated MAL/MRTF-A increases lung colonization by poorly metastatic B16F0 cells. Actin-based cell behaviour and Experimental Metastasis thus require Rho-dependent nuclear signalling through the MRTF-SRF network.
-
myocardin related transcription factors and srf are required for cytoskeletal dynamics and Experimental Metastasis
Nature Cell Biology, 2009Co-Authors: Richard Treisman, Souhila Medjkane, Cedric Gaggioli, Erik Sahai, Cristina PerezsanchezAbstract:By preventing G-actin accumulation, Rho-GTPase promotes the transcriptional activity of myocardin-related transcription factors (MRTFs), known co-factors of serum response factor (SRF). Rho-dependent MRTF expression is required for injected metastatic cell lines to colonize the lung. Rho GTPases control cytoskeletal dynamics through cytoplasmic effectors and regulate transcriptional activation through myocardin-related transcription factors (MRTFs), which are co-activators for serum response factor (SRF). We used RNA interference to investigate the contribution of the MRTF–SRF pathway to cytoskeletal dynamics in MDA-MB-231 breast carcinoma and B16F2 melanoma cells, in which basal MRTF–SRF activity is Rho-dependent. Depletion of MRTFs or SRF reduced cell adhesion, spreading, invasion and motility in culture, without affecting proliferation or inducing apoptosis. MRTF-depleted tumour cell xenografts showed reduced cell motility but proliferated normally. Tumour cells depleted of MRTF or SRF failed to colonize the lung from the bloodstream, being unable to persist after their arrival in the lung. Only a few genes show MRTF-dependent expression in both cell lines. Two of these, MYH9 (NMHCIIa) and MYL9 (MLC2), are also required for invasion and lung colonization. Conversely, expression of activated MAL/MRTF-A increases lung colonization by poorly metastatic B16F0 cells. Actin-based cell behaviour and Experimental Metastasis thus require Rho-dependent nuclear signalling through the MRTF–SRF network.
John L. Francis - One of the best experts on this subject based on the ideXlab platform.
-
Deficiencies in the CD40 and CD154 receptor-ligand system reduce Experimental lung Metastasis.
Clinical & Experimental Metastasis, 2009Co-Authors: Susan B. Ingersoll, Theresa Robson, Florian Länger, Jamie M. Walker, John L. Francis, Todd Meyer, Mildred Amaya, Hina Desai, Ali AmirkhosraviAbstract:It is established that Experimental Metastasis requires platelet activity. CD154 expressed on and released from activated platelets induces an inflammatory response in endothelial cells and monocytes, including tissue factor production. CD154 has also been shown to activate platelets in vitro and promote thrombus stability in vivo. These CD154 effects may be mediated, at least in part, by CD40 signaling on platelets and vascular endothelial cells. We have previously demonstrated prolonged bleeding and PFA-100 closure times in mice deficient for Cd154 or its receptor Cd40. In the present study, we hypothesized that Cd40 and Cd154 promote lung tumor formation in Experimental Metastasis in mice. We created mice doubly deficient in Cd40 and Cd154 (Dbl KO) and found them to be both fertile and viable. Injected tumor cells seeded poorly in mice deficient in Cd40 or Cd154, as well as Dbl KO, compared to wild-type mice. We sought to determine whether blood-borne Cd40 versus endothelial Cd40 contribute differentially to reduced Experimental lung Metastasis, as observed in Cd40 deficient mice. By bone marrow transplantation, we created mice deficient for Cd40 either in the blood compartment but not in the endothelium, or vice versa. We found that mice deficient in blood compartment Cd40 had fewer lung nodules compared to wild-type mice and mice deficient in endothelial Cd40. Our findings suggest an important contribution of the Cd40-Cd154 pathway to Experimental lung Metastasis. Furthermore, the data points to a selective role for peripheral blood cell Cd40 in this process.
-
Experimental Metastasis and primary tumor growth in mice with hemophilia a
Journal of Thrombosis and Haemostasis, 2006Co-Authors: Florian Länger, Ali Amirkhosravi, Susan B. Ingersoll, Jamie M. Walker, B. Spath, B. Eifrig, Carsten Bokemeyer, John L. FrancisAbstract:Summary. During Experimental lung Metastasis, tumor cells adhere to the pulmonary microvasculature and activate coagulation via surface-expressed tissue factor (TF), leading to local fibrin deposition and platelet aggregation. While interventional studies have demonstrated great efficacy of anticoagulants and antiplatelet agents in inhibiting Metastasis, no information is available on how tumor biology may be affected by congenital bleeding disorders such as hemophilia A. We therefore used a syngeneic model to study Experimental Metastasis and primary tumor growth in factor VIII (FVIII)-deficient mice. By conventional reverse transcription-polymerase chain reaction, flow cytometry, and one-stage clotting assays, we demonstrated constitutive expression of TF mRNA, antigen, and procoagulant activity in the murine B16F10 melanoma cell line. In hemophilic mice, B16F10 lung Metastasis was significantly (P < 0.001) enhanced by a single dose of human FVIII (100 U kg−1), suggesting that FVIII played a critical role during the early blood-borne phase of the metastatic cascade. In contrast, lung seeding was significantly (P < 0.05) reduced by lepirudin, a direct thrombin inhibitor, suggesting that thrombin generation contributed to pulmonary Metastasis even in the absence of FVIII. Consistent with this finding, intravenous injection of B16F10 cell-evoked laboratory changes of a hemolytic thrombotic microangiopathy and consumptive coagulopathy in both hemophilic and non-hemophilic mice. Subcutaneous implantation of B16F10 cells into mice with hemophilia A gave rise to primary tumors in an exponential growth pattern similar to that observed in non-hemophilic mice. Although TF expression by B16F10 cells may promote thrombin-dependent Metastasis in mice with hemophilia A, amplification of coagulation by host FVIII appears to be necessary for maximum lung seeding.
-
Tissue factor pathway inhibitor reduces Experimental lung Metastasis of B16 melanoma.
Thrombosis and haemostasis, 2002Co-Authors: Ali Amirkhosravi, Todd Meyer, Mildred Amaya, Hina Desai, Jen Yea Chang, Farooq A. Siddiqui, John L. FrancisAbstract:The importance of tissue factor (TF) in tumor biology has been highlighted by studies suggesting its involvement in cell signaling, Metastasis and angiogenesis. Since many animal studies have shown that anticoagulant therapy can reduce Experimental Metastasis, we studied whether the natural inhibitor of TF-mediated blood coagulation, Tissue Factor Pathway Inhibitor (TFPI), might be similarly effective. Using a murine Experimental model, we found that intravenous injection of recombinant murine TFPI immediately before introduction of tumor cells reduced Metastasis by 83% (P
-
soluble fibrin augments platelet tumor cell adherence in vitro and in vivo and enhances Experimental Metastasis
Clinical & Experimental Metastasis, 1999Co-Authors: John Biggerstaff, Ali Amirkhosravi, Todd Meyer, Farooq A. Siddiqui, N. Seth, M. Amaya, S. Fogarty, John L. FrancisAbstract:There is considerable evidence for a relationship between hemostasis and malignancy. Since platelet adhesion to tumor cells has been implicated in the metastatic process and plasma levels of fibrinogen (Fg) and soluble fibrin (sFn) monomer are increased in cancer, we hypothesized that these molecules might enhance tumor-platelet interaction. We therefore studied binding of sFn monomer to tumor cells in a static microplate adhesion assay and determined the effect of pre-treating tumor cells with sFn on tumor cell-induced thrombocytopenia and Experimental Metastasis. Soluble fibrin (produced by adding thrombin to FXIII- and plasminogen-free Fg in the presence of Gly-Pro-Arg-Pro-amide (GPRP-NH2) significantly increased platelet adherence to tumor cells. This effect was primarily mediated by the integrins alphaIIb beta3 on the platelet and CD 54 (ICAM-1) on the tumor cells. Platelets adhered to untreated A375 cells (28 +/- 8 platelets/tumor cell) and this was not significantly affected by pre-treatment of the tumor cells with fibrinogen or GPRP-NH2. Although thrombin treatment increased adherence, pre-incubation of the tumor cells with sFn resulted in a further increase in platelet binding to tumor cells. In contrast to untreated tumor cells, intravenous injection of sFn-treated A 375 cells reduced the platelet count in anticoagulated mice, supporting the in vitro finding that sFn enhanced tumor cell-platelet adherence. In a more aggressive model of Experimental Metastasis, treating tumor cells with sFn enhanced lung seeding by 65% compared to untreated cells. Extrapolation of our data to the clinical situation suggests that coagulation activation, and subsequent increase in circulating Fn monomer, may enhance platelet adhesion to circulating tumor cells and thereby facilitate metastatic spread.
Mark J. Smyth - One of the best experts on this subject based on the ideXlab platform.
-
Toll-like receptor 3 regulates NK cell responses to cytokines and controls Experimental Metastasis
OncoImmunology, 2015Co-Authors: Camille Guillerey, Melvyn T. Chow, Kim Miles, Jaclyn Sceneay, Stuart D Olver, Kazuyoshi Takeda, Mark J. SmythAbstract:The Toll-like receptor 3 (TLR3) agonist poly(I:C) is a promising adjuvant for cancer vaccines due to its induction of potent antitumor responses occurring primarily through the activation of dendritic cells (DCs) and natural killer (NK) cells. However, little is known about the role of TLR3 sensing of endogenous ligands in innate tumor immunosurveillance. Here, we investigated whether TLR3 could modulate immune responses and facilitate tumor control without administration of an agonist. We observed only limited impact of TLR3 deficiency on spontaneous carcinogenesis and primary growth of B16F10, E0771 or MC38 tumors when injected subcutaneously to mice. Nevertheless, TLR3 was observed to limit Experimental B16F10 lung Metastasis, an immunologic constraint dependent on both IFNγ secretion and NK cells. Interestingly, we observed that NK cells derived from Tlr3 null (Tlr3−/−) mice were hyporesponsive to cytokine stimulation. Indeed, compared with NK cells with intact TLR3, Tlr3−/− NK cells produced signific...
-
cd73 deficient mice have increased antitumor immunity and are resistant to Experimental Metastasis
Cancer Research, 2011Co-Authors: John Stagg, Upulie Divisekera, Helene Duret, Tim Sparwasser, Michele W L Teng, Phillip K Darcy, Mark J. SmythAbstract:CD73 is a cell-surface enzyme that suppresses immune responses by producing extracellular adenosine. In this study, we employed CD73 gene-targeted mice to investigate the role of host-derived CD73 on antitumor immunity and tumor cell Metastasis. We found that CD73 ablation significantly suppressed the growth of ovalbumin-expressing MC38 colon cancer, EG7 lymphoma, AT-3 mammary tumors, and B16F10 melanoma. The protective effect of CD73 deficiency on primary tumors was dependent on CD8(+) T cells and associated with an increased frequency of antigen-specific CD8(+) T cells in peripheral blood and tumors and increased antigen-specific IFN-γ production. Replicate studies in bone marrow chimeras established that both hematopoietic and nonhematopoietic expression of CD73 was important to promote tumor immune escape. Using adoptive reconstitution of T regulatory cell (Treg)-depleted DEREG (depletion of regulatory T cells) mice, we demonstrated that part of the protumorigenic effect of Tregs was dependent on their expression of CD73. CD73-deficient mice were also protected against pulmonary Metastasis of B16F10 melanoma cells after intravenous injection. Unexpectedly, we found that the prometastatic effect of host-derived CD73 was dependent on CD73 expression on nonhematopoietic cells. CD73 expression on nonhematopoietic cells, most likely endothelial cells, was critical for promoting lung Metastasis in a manner independent from immunosuppressive effects. Notably, in vivo blockade of CD73 with a selective inhibitor or anti-CD73 monoclonal antibody significantly reduced tumor growth and Metastasis of CD73-negative tumors. Taken together, our findings indicate that CD73 may be targeted at multiple levels to induce anticancer effects including at the level of tumor cells, Tregs, and nonhematopoietic cells.
Ali Amirkhosravi - One of the best experts on this subject based on the ideXlab platform.
-
Deficiencies in the CD40 and CD154 receptor-ligand system reduce Experimental lung Metastasis.
Clinical & Experimental Metastasis, 2009Co-Authors: Susan B. Ingersoll, Theresa Robson, Florian Länger, Jamie M. Walker, John L. Francis, Todd Meyer, Mildred Amaya, Hina Desai, Ali AmirkhosraviAbstract:It is established that Experimental Metastasis requires platelet activity. CD154 expressed on and released from activated platelets induces an inflammatory response in endothelial cells and monocytes, including tissue factor production. CD154 has also been shown to activate platelets in vitro and promote thrombus stability in vivo. These CD154 effects may be mediated, at least in part, by CD40 signaling on platelets and vascular endothelial cells. We have previously demonstrated prolonged bleeding and PFA-100 closure times in mice deficient for Cd154 or its receptor Cd40. In the present study, we hypothesized that Cd40 and Cd154 promote lung tumor formation in Experimental Metastasis in mice. We created mice doubly deficient in Cd40 and Cd154 (Dbl KO) and found them to be both fertile and viable. Injected tumor cells seeded poorly in mice deficient in Cd40 or Cd154, as well as Dbl KO, compared to wild-type mice. We sought to determine whether blood-borne Cd40 versus endothelial Cd40 contribute differentially to reduced Experimental lung Metastasis, as observed in Cd40 deficient mice. By bone marrow transplantation, we created mice deficient for Cd40 either in the blood compartment but not in the endothelium, or vice versa. We found that mice deficient in blood compartment Cd40 had fewer lung nodules compared to wild-type mice and mice deficient in endothelial Cd40. Our findings suggest an important contribution of the Cd40-Cd154 pathway to Experimental lung Metastasis. Furthermore, the data points to a selective role for peripheral blood cell Cd40 in this process.
-
Experimental Metastasis and primary tumor growth in mice with hemophilia a
Journal of Thrombosis and Haemostasis, 2006Co-Authors: Florian Länger, Ali Amirkhosravi, Susan B. Ingersoll, Jamie M. Walker, B. Spath, B. Eifrig, Carsten Bokemeyer, John L. FrancisAbstract:Summary. During Experimental lung Metastasis, tumor cells adhere to the pulmonary microvasculature and activate coagulation via surface-expressed tissue factor (TF), leading to local fibrin deposition and platelet aggregation. While interventional studies have demonstrated great efficacy of anticoagulants and antiplatelet agents in inhibiting Metastasis, no information is available on how tumor biology may be affected by congenital bleeding disorders such as hemophilia A. We therefore used a syngeneic model to study Experimental Metastasis and primary tumor growth in factor VIII (FVIII)-deficient mice. By conventional reverse transcription-polymerase chain reaction, flow cytometry, and one-stage clotting assays, we demonstrated constitutive expression of TF mRNA, antigen, and procoagulant activity in the murine B16F10 melanoma cell line. In hemophilic mice, B16F10 lung Metastasis was significantly (P < 0.001) enhanced by a single dose of human FVIII (100 U kg−1), suggesting that FVIII played a critical role during the early blood-borne phase of the metastatic cascade. In contrast, lung seeding was significantly (P < 0.05) reduced by lepirudin, a direct thrombin inhibitor, suggesting that thrombin generation contributed to pulmonary Metastasis even in the absence of FVIII. Consistent with this finding, intravenous injection of B16F10 cell-evoked laboratory changes of a hemolytic thrombotic microangiopathy and consumptive coagulopathy in both hemophilic and non-hemophilic mice. Subcutaneous implantation of B16F10 cells into mice with hemophilia A gave rise to primary tumors in an exponential growth pattern similar to that observed in non-hemophilic mice. Although TF expression by B16F10 cells may promote thrombin-dependent Metastasis in mice with hemophilia A, amplification of coagulation by host FVIII appears to be necessary for maximum lung seeding.
-
Tissue factor pathway inhibitor reduces Experimental lung Metastasis of B16 melanoma.
Thrombosis and haemostasis, 2002Co-Authors: Ali Amirkhosravi, Todd Meyer, Mildred Amaya, Hina Desai, Jen Yea Chang, Farooq A. Siddiqui, John L. FrancisAbstract:The importance of tissue factor (TF) in tumor biology has been highlighted by studies suggesting its involvement in cell signaling, Metastasis and angiogenesis. Since many animal studies have shown that anticoagulant therapy can reduce Experimental Metastasis, we studied whether the natural inhibitor of TF-mediated blood coagulation, Tissue Factor Pathway Inhibitor (TFPI), might be similarly effective. Using a murine Experimental model, we found that intravenous injection of recombinant murine TFPI immediately before introduction of tumor cells reduced Metastasis by 83% (P
-
soluble fibrin augments platelet tumor cell adherence in vitro and in vivo and enhances Experimental Metastasis
Clinical & Experimental Metastasis, 1999Co-Authors: John Biggerstaff, Ali Amirkhosravi, Todd Meyer, Farooq A. Siddiqui, N. Seth, M. Amaya, S. Fogarty, John L. FrancisAbstract:There is considerable evidence for a relationship between hemostasis and malignancy. Since platelet adhesion to tumor cells has been implicated in the metastatic process and plasma levels of fibrinogen (Fg) and soluble fibrin (sFn) monomer are increased in cancer, we hypothesized that these molecules might enhance tumor-platelet interaction. We therefore studied binding of sFn monomer to tumor cells in a static microplate adhesion assay and determined the effect of pre-treating tumor cells with sFn on tumor cell-induced thrombocytopenia and Experimental Metastasis. Soluble fibrin (produced by adding thrombin to FXIII- and plasminogen-free Fg in the presence of Gly-Pro-Arg-Pro-amide (GPRP-NH2) significantly increased platelet adherence to tumor cells. This effect was primarily mediated by the integrins alphaIIb beta3 on the platelet and CD 54 (ICAM-1) on the tumor cells. Platelets adhered to untreated A375 cells (28 +/- 8 platelets/tumor cell) and this was not significantly affected by pre-treatment of the tumor cells with fibrinogen or GPRP-NH2. Although thrombin treatment increased adherence, pre-incubation of the tumor cells with sFn resulted in a further increase in platelet binding to tumor cells. In contrast to untreated tumor cells, intravenous injection of sFn-treated A 375 cells reduced the platelet count in anticoagulated mice, supporting the in vitro finding that sFn enhanced tumor cell-platelet adherence. In a more aggressive model of Experimental Metastasis, treating tumor cells with sFn enhanced lung seeding by 65% compared to untreated cells. Extrapolation of our data to the clinical situation suggests that coagulation activation, and subsequent increase in circulating Fn monomer, may enhance platelet adhesion to circulating tumor cells and thereby facilitate metastatic spread.
