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A systems view of epithelialâmesenchymal transition signaling states | Clinical & Experimental Metastasis
Description:
Epithelialâmesenchymal transition (EMT) is an important contributor to the invasion and metastasis of epithelial-derived cancers. While considerable effort has focused in the regulators involved in the transition process, we have focused on consequences of EMT to prosurvival signaling. Changes in distinct metastable and âepigentically-fixedâ EMT states were measured by correlation of protein, phosphoprotein, phosphopeptide and RNA transcript abundance. The assembly of 1167 modulated components into functional systems or machines simplified biological understanding and increased prediction confidence highlighting four functional groups: cell adhesion and migration, metabolism, transcription nodes and proliferation/survival networks. A coordinate metabolic reduction in a cluster of 17 free-radical stress pathway components was observed and correlated with reduced glycolytic and increased oxidative phosphorylation enzyme capacity, consistent with reduced cell cycling and reduced need for macromolecular biosynthesis in the mesenchymal state. An attenuation of EGFR autophosphorylation and a switch from autocrine to paracrine-competent EGFR signaling was implicated in the enablement of tumor cell chemotaxis. A similar attenuation of IGF1R, MET and RON signaling with EMT was observed. In contrast, EMT increased prosurvival autocrine IL11/IL6-JAK2-STAT signaling, autocrine fibronectin-integrin Îą5β1 activation, autocrine Axl/Tyro3/PDGFR/FGFR RTK signaling and autocrine TGFβR signaling. A relatively uniform loss of polarity and cellâcell junction linkages to actin cytoskeleton and intermediate filaments was measured at a systems level. A more heterogeneous gain of ECM remodeling and associated with invasion and migration was observed. Correlation to stem cell, EMT, invasion and metastasis datasets revealed the greatest similarity with normal and cancerous breast stem cell populations, CD49fhi/EpCAM-/lo and CD44hi/CD24lo, respectively.
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Keywords {đ}
emt, cell, google, scholar, pubmed, cells, cas, cancer, epithelial, mesenchymal, tumor, increased, signaling, models, transition, supplementary, protein, phosphorylation, state, egfr, networks, observed, components, activation, fig, metastable, snail, tgfβ, proteins, res, states, data, autocrine, table, expression, phenotype, mesenchymallike, zeb, survival, receptor, abundance, loss, growth, factor, resistance, genes, systems, rna, nsclc, lines,
Topics {âď¸}
included autocrine il11/il6-gp130/jak2/stat tgf-beta-induced epithelial-mesenchymal transition time-lapse live-cell imaging itraq 2d-lc-ms/ms ras-induced raf-mek-erk activation proteomic lc-ms/ms analysis autocrine il6st-jak-stat signaling block nfe2l2/l3-mediated increases itraq-2dlc-ms/ms colony-stimulating factor-1 receptor jak/stat signaling pathways il11/il6-jak/stat fibronectin-mediated Îą5β1-integrin activation large-scale transcriptional profiling ďż˝epigenetically-fixedâ nsclc lines post-transcriptional rna processing pure spindle-cell carcinomas control n1/control n2 reactive oxygen species epithelial-derived carcinoma cells article download pdf epigenetically-fixed chromatin states growth factor receptor active multi-directional communication egf-mediated directional chemotaxis pro-inflammatory cytokine pge2 tumor micro-environment play ďż˝epigentically-fixedâ emt states receptor tyrosine kinases restores cellâcell junctions weaken cellâcell junctions serine-threonine kinases pak1 epigenically-fixed emt states large-scale microarray analysis ďż˝epigenetically-fixedâ emt state epithelial-derived tumor cells elevated sdf-1/cxcl12 secretion hepatocyte growth factor cell cycle kinases integrin/cadherin switching allowing mesenchymal transition-induced regulator lc-tandem ms lacked e-cadherin expression fixed-state mesenchymal lines notably glutathione s-transferase induce epithelial-mesenchymal transition forms cellâcell junctions cellâcell junction linkages epithelial cellâcell junctions h358/doxzeb1 cells show
Questions {â}
- Another question that arises from these findings is what is promoting cell survival and preventing anoikis or senescence, in the absence of EGFR family, IGF1R, Met and Ron signaling, important survival networks for normal epithelium?
- Blaukovitsch M et al (2006) Sarcomatoid carcinomas of the lungâare these histogenetically heterogeneous tumors?
- Peinado H, Olmeda D, Cano A (2007) Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype?
- Trachootham D, Alexandre J, Huang P (2009) Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach?
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headline:A systems view of epithelialâmesenchymal transition signaling states
description:Epithelialâmesenchymal transition (EMT) is an important contributor to the invasion and metastasis of epithelial-derived cancers. While considerable effort has focused in the regulators involved in the transition process, we have focused on consequences of EMT to prosurvival signaling. Changes in distinct metastable and âepigentically-fixedâ EMT states were measured by correlation of protein, phosphoprotein, phosphopeptide and RNA transcript abundance. The assembly of 1167 modulated components into functional systems or machines simplified biological understanding and increased prediction confidence highlighting four functional groups: cell adhesion and migration, metabolism, transcription nodes and proliferation/survival networks. A coordinate metabolic reduction in a cluster of 17 free-radical stress pathway components was observed and correlated with reduced glycolytic and increased oxidative phosphorylation enzyme capacity, consistent with reduced cell cycling and reduced need for macromolecular biosynthesis in the mesenchymal state. An attenuation of EGFR autophosphorylation and a switch from autocrine to paracrine-competent EGFR signaling was implicated in the enablement of tumor cell chemotaxis. A similar attenuation of IGF1R, MET and RON signaling with EMT was observed. In contrast, EMT increased prosurvival autocrine IL11/IL6-JAK2-STAT signaling, autocrine fibronectin-integrin Îą5β1 activation, autocrine Axl/Tyro3/PDGFR/FGFR RTK signaling and autocrine TGFβR signaling. A relatively uniform loss of polarity and cellâcell junction linkages to actin cytoskeleton and intermediate filaments was measured at a systems level. A more heterogeneous gain of ECM remodeling and associated with invasion and migration was observed. Correlation to stem cell, EMT, invasion and metastasis datasets revealed the greatest similarity with normal and cancerous breast stem cell populations, CD49fhi/EpCAM-/lo and CD44hi/CD24lo, respectively.
datePublished:2010-12-31T00:00:00Z
dateModified:2010-12-31T00:00:00Z
pageStart:137
pageEnd:155
license:https://creativecommons.org/licenses/by-nc/2.0
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keywords:
Cell polarity
Drug resistance
Epithelial mesenchymal transition
EMT
Non-small cell lung cancer
Phosphorylation
Snail
Systems biology
TGF beta
Zeb1
Kinase
Cancer Research
Biomedicine
general
Oncology
Hematology
Surgical Oncology
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headline:A systems view of epithelialâmesenchymal transition signaling states
description:Epithelialâmesenchymal transition (EMT) is an important contributor to the invasion and metastasis of epithelial-derived cancers. While considerable effort has focused in the regulators involved in the transition process, we have focused on consequences of EMT to prosurvival signaling. Changes in distinct metastable and âepigentically-fixedâ EMT states were measured by correlation of protein, phosphoprotein, phosphopeptide and RNA transcript abundance. The assembly of 1167 modulated components into functional systems or machines simplified biological understanding and increased prediction confidence highlighting four functional groups: cell adhesion and migration, metabolism, transcription nodes and proliferation/survival networks. A coordinate metabolic reduction in a cluster of 17 free-radical stress pathway components was observed and correlated with reduced glycolytic and increased oxidative phosphorylation enzyme capacity, consistent with reduced cell cycling and reduced need for macromolecular biosynthesis in the mesenchymal state. An attenuation of EGFR autophosphorylation and a switch from autocrine to paracrine-competent EGFR signaling was implicated in the enablement of tumor cell chemotaxis. A similar attenuation of IGF1R, MET and RON signaling with EMT was observed. In contrast, EMT increased prosurvival autocrine IL11/IL6-JAK2-STAT signaling, autocrine fibronectin-integrin Îą5β1 activation, autocrine Axl/Tyro3/PDGFR/FGFR RTK signaling and autocrine TGFβR signaling. A relatively uniform loss of polarity and cellâcell junction linkages to actin cytoskeleton and intermediate filaments was measured at a systems level. A more heterogeneous gain of ECM remodeling and associated with invasion and migration was observed. Correlation to stem cell, EMT, invasion and metastasis datasets revealed the greatest similarity with normal and cancerous breast stem cell populations, CD49fhi/EpCAM-/lo and CD44hi/CD24lo, respectively.
datePublished:2010-12-31T00:00:00Z
dateModified:2010-12-31T00:00:00Z
pageStart:137
pageEnd:155
license:https://creativecommons.org/licenses/by-nc/2.0
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keywords:
Cell polarity
Drug resistance
Epithelial mesenchymal transition
EMT
Non-small cell lung cancer
Phosphorylation
Snail
Systems biology
TGF beta
Zeb1
Kinase
Cancer Research
Biomedicine
general
Oncology
Hematology
Surgical Oncology
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