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Time course of TGFbeta induced epithelial mesenchymal transition (EMT) in H358 NSCLC cells.

ABSTRACT: The capacity of cancer cells to undergo epithelial mesenchymal trans-differentiation has been implicated as a factor driving metastasis, through the acquisition of enhanced migratory/invasive cell programs and the engagement of anti-apoptotic mechanisms promoting drug and radiation resistance. Our aim was to define molecular signaling changes associated with mesenchymal trans-differentiation in two KRas mutant NSCLC models. We focused on central transcription and epigenetic regulators predicted to be important for mesenchymal cell survival.

ORGANISM(S): Homo sapiens

PROVIDER: GSE125365 | GEO | 2019/01/23

REPOSITORIES: GEO

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Project description:Epithelial – mesenchymal 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 ‘epigentically-fixed’ 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 activation, autocrine Axl/Tyro3/PDGFR/FGFR RTK signaling and autocrine TGF-R signaling. A relatively uniform loss of polarity and cell-cell 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. Thomson, S., Petti, F., Sujka-Kwok, I., Mercado, P., Bean, J., Monaghan, M., Seymour, S.L., Argast, G., Epstein, D. and Haley, J.D. (2011). ‘A systems view of epithelial - mesenchymal transition signaling states’ Clin. Exp. Metastasis 28, 137-55.

Project description:Importance of growth factor (GF) signaling in cancer progression is widely acknowledged. Transforming growth factor beta (TGFβ) and and hepa- tocyte growth factor (HGF) are known to play a key role in epithelial-to- mesenchymal transition (EMT) and metastatic cell transformation that are characterized by distinctive alterations in cell mechanical architecture and behavior towards a more robust and motile single cell phenotype. How- ever, molecular mechanisms mediating cancer type specific enhancement of cell mechanical properties in response to growth factors remain unlighted. Here, we combine high-throughput mechanical cell phenotyping, microarray analysis and gene-silencing to dissect molecular mediators of GF-induces cell mechanical enhancement in non-small-cell lung adenocarcinoma (NSCLC). Our experimental results show that both growth factors elevate cell rigidity, size and migratory activity, however, effects of TGFβ stimulation on cell mechanical phenotype and differential gene expression turn out to be significantly stronger. Our microarray analysis reveals that TGFβ-treated NSCLC cells exhibit upregulation of migration-, adhesion-related and down- regulation of cytokinesis-related groups of genes. In addition to vimentin, a canonical marker of EMT, a large number of cytoskeletal and motor proteins including previously reported MYL9, MYLK, TMP1 but also less-known un- conventional myosins are overexpressed in lung adenocarcenoma cells upon treatment with TGFβ. Selective probing of gene-silenced cells lead to identi- fication of unconventional myosin MYH15 as a novel mediator of elevated cell rigidity and invasiveness in TGFβ-stimulated NSCLC cells. In comparison to TGFβ, HGF-treated NSCLC cells respond with upregulation of a relatively small number of genes that are related to actin cyskeleton, microtubules and caveolae. Our results provide insights into phenotypic effects and molecular mechanisms of TGFβ- and HGF-induced mesenchymal cell transformation in NSCLC, and suggest that mediators of cell mechanical enhancement such as unconventional cytoskeletal and motor proteins represent promising phar- maceutical targets for restraining invasive spread of lung cancer.

Project description:Epithelial/mesenchymal transition (EMT) is associated with loss of cell adhesion molecules, such as E-cadherin, and increased invasion, migration, and proliferation in epithelial cancers. In non-small cell lung cancer (NSCLC), EMT is associated with greater resistance to EGFR inhibitors. However, its potential to predict response to other targeted drugs or chemotherapy has not been well characterized. The goal of this study was to develop a robust, platform-independent EMT gene expression signature and to investigate the association of EMT and drug response in NSCLC. A 76-gene EMT signature was derived in 54 DNA-fingerprinted NSCLC cell lines and tested in an independent set of cell lines and in NSCLC patients from the BATTLE clinical trial. The signature classified cell lines as epithelial or mesenchymal independent of the microarray platform and correlated strongly with E-cadherin protein levels, as measured by reverse phase protein array. Higher protein expression of Rab25 (in epithelial lines) and Axl (in mesenchymal lines), two signature genes associated with in EMT in other cancer types, was also confirmed. Mesenchymal cell lines demonstrated significantly greater resistance to EGFR inhibition, independent of EGFR mutation status and were more resistant to drugs targeting the PI3K/Akt pathway. We observed no association between EMT and response to cytotoxic chemotherapies, including cisplatin, pemetrexed, and docetaxel monotherapy and/or doublets (p-values ≥0.2). In NSCLC patients, the EMT signature predicted 8-week disease control in the erlotinib arm, but not in other treatment arms. In conclusion, we have developed a robust EMT signature that predicts resistance to EGFR inhibitors and PI3K/Akt pathway inhibitors. Gene expression profiles were measured in 131 core biopsies from patients with refractory non-small cell lung cancer in the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial. We used the BATTLE dataset to test an EMT gene expression signature trained in cell lines and independant of the microarray platform.

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Time course of TGFbeta induced epithelial mesenchymal transition (EMT) in H358 NSCLC cells.

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