The Experts below are selected from a list of 186 Experts worldwide ranked by ideXlab platform

Karl Blirando - One of the best experts on this subject based on the ideXlab platform.

  • Slug a cancer related Transcription Factor is involved in vascular smooth muscle cell transdifferentiation induced by platelet derived growth Factor bb during atherosclerosis
    Journal of the American Heart Association, 2020
    Co-Authors: Nahema Ledard, Alexandrine Liboz, Bertrand Blondeau, Mégane Babiak, Célia Moulin, Benjamin Vallin, Isabelle Guillas, Véronique Mateo, Claire Jumeau, Karl Blirando
    Abstract:

    Background Heart attacks and stroke often result from occlusive thrombi following the rupture of vulnerable atherosclerotic plaques. Vascular smooth muscle cells (VSMCs) play a pivotal role in plaque vulnerability because of their switch towards a proinflammatory/macrophage-like phenotype when in the context of atherosclerosis. The prometastatic Transcription Factor Slug/Snail2 is a critical regulator of cell phenotypic transition. Here, we aimed to investigate the role of Slug in the transdifferentiation process of VSMCs occurring during atherogenesis. Methods and Results In rat and human primary aortic smooth muscle cells, Slug protein expression is strongly and rapidly increased by platelet-derived growth Factor-BB (PDGF-BB). PDGF-BB increases Slug protein without affecting mRNA levels indicating that this growth Factor stabilizes Slug protein. Immunocytochemistry and subcellular fractionation experiments reveal that PDGF-BB triggers a rapid accumulation of Slug in VSMC nuclei. Using pharmacological tools, we show that the PDGF-BB-dependent mechanism of Slug stabilization in VSMCs involves the extracellular signal-regulated kinase 1/2 pathway. Immunohistochemistry experiments on type V and type VI atherosclerotic lesions of human carotids show smooth muscle-specific myosin heavy chain-/Slug-positive cells surrounding the prothrombotic lipid core. In VSMCs, Slug siRNAs inhibit prostaglandin E2 secretion and prevent the inhibition of cholesterol efflux gene expression mediated by PDGF-BB, known to be involved in plaque vulnerability and/or thrombogenicity. Conclusions Our results highlight, for the first time, a role of Slug in aortic smooth muscle cell transdifferentiation and enable us to consider Slug as an actor playing a role in the atherosclerotic plaque progression towards a life-threatening phenotype. This also argues for common features between acute cardiovascular events and cancer.

Dimitris Anastassiou - One of the best experts on this subject based on the ideXlab platform.

  • a multi cancer mesenchymal transition gene expression signature is associated with prolonged time to recurrence in glioblastoma
    PLOS ONE, 2012
    Co-Authors: Weiyi Cheng, Jessica J Kandel, Darrell J Yamashiro, Peter Canoll, Dimitris Anastassiou
    Abstract:

    A stage-associated gene expression signature of coordinately expressed genes, including the Transcription Factor Slug (SNAI2) and other epithelial-mesenchymal transition (EMT) markers has been found present in samples from publicly available gene expression datasets in multiple cancer types, including nonepithelial cancers. The expression levels of the co-expressed genes vary in a continuous and coordinate manner across the samples, ranging from absence of expression to strong co-expression of all genes. These data suggest that tumor cells may pass through an EMT-like process of mesenchymal transition to varying degrees. Here we show that, in glioblastoma multiforme (GBM), this signature is associated with time to recurrence following initial treatment. By analyzing data from The Cancer Genome Atlas (TCGA), we found that GBM patients who responded to therapy and had long time to recurrence had low levels of the signature in their tumor samples (P = 3×10−7). We also found that the signature is strongly correlated in gliomas with the putative stem cell marker CD44, and is highly enriched among the differentially expressed genes in glioblastomas vs. lower grade gliomas. Our results suggest that long delay before tumor recurrence is associated with absence of the mesenchymal transition signature, raising the possibility that inhibiting this transition might improve the durability of therapy in glioma patients.

  • human cancer cells express Slug based epithelial mesenchymal transition gene expression signature obtained in vivo
    BMC Cancer, 2011
    Co-Authors: Dimitris Anastassiou, Weiyi Cheng, Darrell J Yamashiro, Peter Canoll, Viktoria Rumjantseva, Jianzhong Huang, Jessica J Kandel
    Abstract:

    Background: The biological mechanisms underlying cancer cell motility and invasiveness remain unclear, although it has been hypothesized that they involve some type of epithelial-mesenchymal transition (EMT). Methods: We used xenograft models of human cancer cells in immunocompromised mice, profiling the harvested tumors separately with species-specific probes and computationally analyzing the results. Results: Here we show that human cancer cells express in vivo a precise multi-cancer invasion-associated gene expression signature that prominently includes many EMT markers, among them the Transcription Factor Slug, fibronectin, and a-SMA. We found that human, but not mouse, cells express the signature and Slug is the only upregulated EMT-inducing Transcription Factor. The signature is also present in samples from many publicly available cancer gene expression datasets, suggesting that it is produced by the cancer cells themselves in multiple cancer types, including nonepithelial cancers such as neuroblastoma. Furthermore, we found that the presence of the signature in human xenografted cells was associated with a downregulation of adipocyte markers in the mouse tissue adjacent to the invasive tumor, suggesting that the signature is triggered by contextual microenvironmental interactions when the cancer cells encounter adipocytes, as previously reported. Conclusions: The known, precise and consistent gene composition of this cancer mesenchymal transition signature, particularly when combined with simultaneous analysis of the adjacent microenvironment, provides unique opportunities for shedding light on the underlying mechanisms of cancer invasiveness as well as identifying potential diagnostic markers and targets for metastasis-inhibiting therapeutics.

Jessica J Kandel - One of the best experts on this subject based on the ideXlab platform.

  • a multi cancer mesenchymal transition gene expression signature is associated with prolonged time to recurrence in glioblastoma
    PLOS ONE, 2012
    Co-Authors: Weiyi Cheng, Jessica J Kandel, Darrell J Yamashiro, Peter Canoll, Dimitris Anastassiou
    Abstract:

    A stage-associated gene expression signature of coordinately expressed genes, including the Transcription Factor Slug (SNAI2) and other epithelial-mesenchymal transition (EMT) markers has been found present in samples from publicly available gene expression datasets in multiple cancer types, including nonepithelial cancers. The expression levels of the co-expressed genes vary in a continuous and coordinate manner across the samples, ranging from absence of expression to strong co-expression of all genes. These data suggest that tumor cells may pass through an EMT-like process of mesenchymal transition to varying degrees. Here we show that, in glioblastoma multiforme (GBM), this signature is associated with time to recurrence following initial treatment. By analyzing data from The Cancer Genome Atlas (TCGA), we found that GBM patients who responded to therapy and had long time to recurrence had low levels of the signature in their tumor samples (P = 3×10−7). We also found that the signature is strongly correlated in gliomas with the putative stem cell marker CD44, and is highly enriched among the differentially expressed genes in glioblastomas vs. lower grade gliomas. Our results suggest that long delay before tumor recurrence is associated with absence of the mesenchymal transition signature, raising the possibility that inhibiting this transition might improve the durability of therapy in glioma patients.

  • human cancer cells express Slug based epithelial mesenchymal transition gene expression signature obtained in vivo
    BMC Cancer, 2011
    Co-Authors: Dimitris Anastassiou, Weiyi Cheng, Darrell J Yamashiro, Peter Canoll, Viktoria Rumjantseva, Jianzhong Huang, Jessica J Kandel
    Abstract:

    Background: The biological mechanisms underlying cancer cell motility and invasiveness remain unclear, although it has been hypothesized that they involve some type of epithelial-mesenchymal transition (EMT). Methods: We used xenograft models of human cancer cells in immunocompromised mice, profiling the harvested tumors separately with species-specific probes and computationally analyzing the results. Results: Here we show that human cancer cells express in vivo a precise multi-cancer invasion-associated gene expression signature that prominently includes many EMT markers, among them the Transcription Factor Slug, fibronectin, and a-SMA. We found that human, but not mouse, cells express the signature and Slug is the only upregulated EMT-inducing Transcription Factor. The signature is also present in samples from many publicly available cancer gene expression datasets, suggesting that it is produced by the cancer cells themselves in multiple cancer types, including nonepithelial cancers such as neuroblastoma. Furthermore, we found that the presence of the signature in human xenografted cells was associated with a downregulation of adipocyte markers in the mouse tissue adjacent to the invasive tumor, suggesting that the signature is triggered by contextual microenvironmental interactions when the cancer cells encounter adipocytes, as previously reported. Conclusions: The known, precise and consistent gene composition of this cancer mesenchymal transition signature, particularly when combined with simultaneous analysis of the adjacent microenvironment, provides unique opportunities for shedding light on the underlying mechanisms of cancer invasiveness as well as identifying potential diagnostic markers and targets for metastasis-inhibiting therapeutics.

Nahema Ledard - One of the best experts on this subject based on the ideXlab platform.

  • Slug a cancer related Transcription Factor is involved in vascular smooth muscle cell transdifferentiation induced by platelet derived growth Factor bb during atherosclerosis
    Journal of the American Heart Association, 2020
    Co-Authors: Nahema Ledard, Alexandrine Liboz, Bertrand Blondeau, Mégane Babiak, Célia Moulin, Benjamin Vallin, Isabelle Guillas, Véronique Mateo, Claire Jumeau, Karl Blirando
    Abstract:

    Background Heart attacks and stroke often result from occlusive thrombi following the rupture of vulnerable atherosclerotic plaques. Vascular smooth muscle cells (VSMCs) play a pivotal role in plaque vulnerability because of their switch towards a proinflammatory/macrophage-like phenotype when in the context of atherosclerosis. The prometastatic Transcription Factor Slug/Snail2 is a critical regulator of cell phenotypic transition. Here, we aimed to investigate the role of Slug in the transdifferentiation process of VSMCs occurring during atherogenesis. Methods and Results In rat and human primary aortic smooth muscle cells, Slug protein expression is strongly and rapidly increased by platelet-derived growth Factor-BB (PDGF-BB). PDGF-BB increases Slug protein without affecting mRNA levels indicating that this growth Factor stabilizes Slug protein. Immunocytochemistry and subcellular fractionation experiments reveal that PDGF-BB triggers a rapid accumulation of Slug in VSMC nuclei. Using pharmacological tools, we show that the PDGF-BB-dependent mechanism of Slug stabilization in VSMCs involves the extracellular signal-regulated kinase 1/2 pathway. Immunohistochemistry experiments on type V and type VI atherosclerotic lesions of human carotids show smooth muscle-specific myosin heavy chain-/Slug-positive cells surrounding the prothrombotic lipid core. In VSMCs, Slug siRNAs inhibit prostaglandin E2 secretion and prevent the inhibition of cholesterol efflux gene expression mediated by PDGF-BB, known to be involved in plaque vulnerability and/or thrombogenicity. Conclusions Our results highlight, for the first time, a role of Slug in aortic smooth muscle cell transdifferentiation and enable us to consider Slug as an actor playing a role in the atherosclerotic plaque progression towards a life-threatening phenotype. This also argues for common features between acute cardiovascular events and cancer.

John R Hawse - One of the best experts on this subject based on the ideXlab platform.

  • kruppel like Transcription Factor klf10 suppresses tgfβ induced epithelial to mesenchymal transition via a negative feedback mechanism
    Cancer Research, 2017
    Co-Authors: Vivek Mishra, Malayannan Subramaniam, Vijayalakshmi Kari, Kevin S Pitel, Simon J Baumgart, Ryan M Naylor, Sankari Nagarajan, Florian Wegwitz, V Ellenrieder, John R Hawse
    Abstract:

    TGFβ-SMAD signaling exerts a contextual effect that suppresses malignant growth early in epithelial tumorigenesis but promotes metastasis at later stages. Longstanding challenges in resolving this functional dichotomy may uncover new strategies to treat advanced carcinomas. The Kruppel-like Transcription Factor KLF10 is a pivotal effector of TGFβ/SMAD signaling that mediates anti-proliferative effects of TGFβ. In this study, we show how KLF10 opposes the pro-metastatic effects of TGFβ by limiting its ability to induce epithelial-to-mesenchymal transition (EMT). KLF10 depletion accentuated induction of EMT as assessed by multiple metrics. KLF10 occupied GC-rich sequences in the promoter region of the EMT-promoting Transcription Factor Slug/SNAI2, repressing its Transcription by recruiting HDAC1 and licensing the removal of activating histone acetylation marks. In clinical specimens of lung adenocarcinoma, low KLF10 expression associated with decreased patient survival, consistent with a pivotal role for KLF10 in distinguishing the anti-proliferative versus pro-metastatic functions of TGFβ. Our results establish that KLF10 functions to suppress TGFβ-induced EMT, establishing a molecular basis for the dichotomy of TGFβ function during tumor progression.

  • kruppel like Transcription Factor klf10 suppresses tgfβ induced epithelial to mesenchymal transition via a negative feedback mechanism
    Cancer Research, 2017
    Co-Authors: Vivek Mishra, Malayannan Subramaniam, Vijayalakshmi Kari, Kevin S Pitel, Simon J Baumgart, Ryan M Naylor, Sankari Nagarajan, Florian Wegwitz, V Ellenrieder, John R Hawse
    Abstract:

    TGFβ-SMAD signaling exerts a contextual effect that suppresses malignant growth early in epithelial tumorigenesis but promotes metastasis at later stages. Longstanding challenges in resolving this functional dichotomy may uncover new strategies to treat advanced carcinomas. The Kruppel-like Transcription Factor, KLF10, is a pivotal effector of TGFβ/SMAD signaling that mediates antiproliferative effects of TGFβ. In this study, we show how KLF10 opposes the prometastatic effects of TGFβ by limiting its ability to induce epithelial-to-mesenchymal transition (EMT). KLF10 depletion accentuated induction of EMT as assessed by multiple metrics. KLF10 occupied GC-rich sequences in the promoter region of the EMT-promoting Transcription Factor Slug/SNAI2, repressing its Transcription by recruiting HDAC1 and licensing the removal of activating histone acetylation marks. In clinical specimens of lung adenocarcinoma, low KLF10 expression associated with decreased patient survival, consistent with a pivotal role for KLF10 in distinguishing the antiproliferative versus prometastatic functions of TGFβ. Our results establish that KLF10 functions to suppress TGFβ-induced EMT, establishing a molecular basis for the dichotomy of TGFβ function during tumor progression. Cancer Res; 77(9); 2387-400. ©2017 AACR.