Transforming Growth Factor β-Induced Epithelial-to-Mesenchymal Signature Predicts Metastasis-Free Survival in Non-Small Cell Lung Cancer.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE114761 | GEO | 2019/02/13
REPOSITORIES: GEO
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Project description:Earlier studies had shown that side population cells isolated from established non-small cell lung cancer (NSCLC) cell lines exhibit cancer stem cell properties. Microarray data from side population (SP) and main population (MP) cells isolated from 4 NSCLC lines (A549, H1650, H460, H1975) were used to examine gene expression profiles associated with stemness. Total RNA extracted from SP and MP samples were used to generate cRNA targets, which were hybridized to Human Genome U133 Plus 2.0 probe arrays. Raw data was processed and the mean center expression level for each gene was determined. Four cell lines (A549, H1650, H460, H1975), each having 1 SP and 1 MP sample.
2012-06-30 | E-GEOD-36821 | biostudies-arrayexpress
Project description:Uncontrolled Transforming growth factor-beta (TGFβ) signaling promotes aggressive metastatic properties in late-stage breast cancers. However, how TGFβ-mediated cues are directed to induce late-stage tumorigenic events is poorly understood, particularly given that TGFβ has clear tumor suppressing activity in other contexts. Here we demonstrate that the transcriptional regulators TAZ and YAP (TAZ/YAP), key effectors of the Hippo pathway, are necessary to promote and maintain TGFβ-induced tumorigenic phenotypes in breast cancer cells. Interactions between TAZ/YAP, TGFβ-activated SMAD2/3, and TEAD transcription factors reveal convergent roles for these factors in the nucleus. Genome-wide expression analyses indicate that TAZ/YAP, TEADs and TGFβ-induced signals coordinate a specific pro-tumorigenic transcriptional program. Importantly, genes cooperatively regulated by TAZ/YAP, TEAD, and TGFβ, such as the novel targets NEGR1 and UCA1, are necessary for maintaining tumorigenic activity in metastatic breast cancer cells. Nuclear TAZ/YAP also cooperate with TGFβ signaling to promote phenotypic and transcriptional changes in non-tumorigenic cells to overcome TGFβ repressive effects. Our work thus identifies crosstalk between nuclear TAZ/YAP and TGFβ signaling in breast cancer cells, revealing novel insight into late-stage disease-driving mechanisms. Expression profiling was conducted following the repression of the transcriptional regulators TAZ and YAP (TAZ/YAP), the TEAD family of transcription factors (TEAD1/2/3/4), or the TGFb signaling pathway (with SB-431542, an inhibitor of the TBRI recpeptor) in human MDA-MB-231-LM2 breast cancer cells treated with TGFβ1. Human MDA-MB-231-LM2-4 breast cancer cells were transfected with control siRNA, or siRNAs targeting TAZ/YAP or all four TEADs and were treated 24 hours later with 500pM TGFβ1 or 5mM SB-431542 for an additional 24 hours. Total RNA was isolated and twelve microarrays in total were performed, with each condition carried out three times on separate days. The Boston University Microarray Core generated the data using the Affymetrix Human Gene 1.0 St Array.
2014-04-02 | E-GEOD-56445 | biostudies-arrayexpress
Project description:Earlier studies had shown that side population cells isolated from established non-small cell lung cancer (NSCLC) cell lines exhibit cancer stem cell properties. Microarray data from side population (SP) and main population (MP) cells isolated from 4 NSCLC lines (A549, H1650, H460, H1975) were used to examine gene expression profiles associated with stemness. Total RNA extracted from SP and MP samples were used to generate cRNA targets, which were hybridized to Human Genome U133 Plus 2.0 probe arrays. Raw data was processed and the mean center expression level for each gene was determined.
2012-07-01 | GSE36821 | GEO
Project description:Transforming Growth Factor β-Induced Epithelial-to-Mesenchymal Signature Predicts Metastasis-Free Survival in Non-Small Cell Lung Cancer.
| PRJNA472577 | ENA
Project description:Transforming growth factor beta (TGFβ) plays a key role in regulating epithelial-to-mesenchymal transition (EMT). A gene expression signature (TGFβ-EMT) associated with TGFβ-induced EMT activities was developed using human Non-Small Cell Lung Carcinoma (NSCLC) cells treated with TGFβ-1 and subjected to Affymetrix microarray analysis. The final 105-probeset TGFβ-EMT signature covers 77 genes, and a NanoString assay utilized a subset of 60 of these genes (TGFβ-EMTN signature). We found that the TGFβ-EMT and TGFβ-EMTN gene signatures predicted overall survival (OS) and metastasis-free survival (MFS). The TGFβ-EMT signature was validated as prognostic of 5-year MFS in 3 cohorts: a 133 NSCLC tumor dataset (P = 0.0002), a NanoString assays of RNA isolated from formalin-fixed paraffin-embedded samples from these same tumors (P = 0.0015), and a previously published NSCLC MFS dataset (P = 0.0015). The separation between high and low metastasis signature scores was higher at 3 years (ΔMFS TGFβ-EMT = -28.6%; ΔMFS TGFβ-EMTN = -25.2%) than at 5 years (ΔMFS TGFβ-EMT = -18.6%; ΔMFS TGFβ-EMTN = -11.8%). In addition, the TGFβ-EMT signature correlated with whether the cancer had already metastasized or not at time of surgery in a colon cancer cohort. The results show that the TGFβ-EMT signature successfully discriminated lung cancer cell lines capable of undergoing EMT in response to TGFβ-1 and predicts MFS in lung adenocarcinomas. Thus, the TGFβ-EMT signature has the potential to be developed as a clinically relevant predictive biomarker, for example to identify those patients with resected early stage lung cancer who may benefit from adjuvant therapy.
| S-EPMC6368226 | biostudies-literature
Project description:Glioblastoma stem cells (GSCs) fate is controlled by environmental cues, among which cytokines play a crucial role. The transforming growth factor β (TGFβ) family signaling pathways controls GSCs. On one hand, TGFβ promotes cell proliferation in GBM, it induces the expression of platelet-derived growth factor-B (PDGFB). Moreover, TGFβ, via its signaling mediators Smad2/3, induces the expression of the cytokine leukemia inhibitory factor (LIF) and Sox4, which in turn enhances the expression of the stem cell transcription factor Sox2; this increases the self-renewal capacity of the GSCs and their stemness characteristics, and enhances the GSC tumor-initiating potential. On the other hand, Bone morphogenic proteins (BMPs) are known to promote GSC differentiation towards the astrocytic phenotype. To further understand which genes are regulated by TGFβ and BMP7 in GSCs we performed a microarray in the Affymetrix HTA2 platform in three different glioblastoma cell line, U2987, and two patient-derived glioblastoma stem cells, U3031MG and U3034MG, in the presence or absence of 5 ng/ml of TGFβ or 30 ng/ml BMP7 for 24 h, three biological replicates per condition.
2020-09-01 | E-MTAB-9076 | biostudies-arrayexpress
Project description:Radiotherapy is standard of care for inoperable non-small cell lung cancers (NSCLC) but adenocarcinoma NSCLC respond more poorly than squamous cell NSCLC. Transforming growth factor β (TGFβ) activity is induced by radiation and plays a recently recognized role in the DNA damage response. Here we show in murine lung tumor model that radiation activates TGFβ acutely and persistently and that TGFβ neutralizing antibody, 1D11, systemic treatment increased tumor control following either fractionated or single high dose radiation regimes. TGFβ dependent genes in the irradiated tumor indicated crosstalk between innate and adaptive immunity but therapeutic benefit of 1D11 in irradiated tumors in immunocompromised mice suggested that innate immune cells are more influential than the adaptive immune response. Irradiated tumors in which TGFβ was blocked were highly hypoxic, exhibit pronounced microvascular damage and promoted neither cancer-associated fibroblasts nor recruit bone marrow derived cells (BMDC). Tumor educated immature BMDC were significant sources of TGFβ and inhibiting BMDC recruitment achieved tumor growth control in response to RT comparable to TGFβ inhibition. Thus, radiation-induced TGFβ both compromises tumor control by RT and promotes reestablishment of the tumor microenvironment. Concordant with the critical role of TGFβ activity in RT, radiation resistant NSCLC adenocarcinomas exhibit higher TGFβ activity compared to squamous cell NSCLC, which suggests a rationale for using TGFβ inhibition to augment radiotherapy.
2015-12-15 | GSE73095 | GEO
Project description:<p><strong>OBJECTIVES:</strong> High activity of Indoleamine 2,3-dioxygenase1 (IDO1) in lung cancer patients converts tryptophan (Trp), which is the essential amino acid for T cell metabolism, to kynurenine (Kyn) and consequently suppresses anti-tumor immune responses. We aimed to track the dynamics of IDO1 activity in stage III non-small cell lung cancer (NSCLC) patients who received first-line radiotherapy (RT) and explore its association with survival outcomes.</p><p><strong>MATERIALS AND METHODS:</strong> Systemic IDO1 activity was calculated by Kyn:Trp ratio. Plasma levels of Kyn and Trp in 113 thoracic RT-received stage III NSCLC patients were measured by high-performance liquid chromatography before the initiation of RT. Dynamic change of IDO1 activity was followed in 24 patients by measuring Kyn:Trp ratio before, during and after RT administration.</p><p><strong>RESULTS:</strong> In 24 patients with dynamic tracking of plasma IDO1 activity, there was no significant alterations observed among the 3 time points (Friedman test, p=0.13). The changing pattern of Kyn:Trp ratio was divided into 4 groups: decreased consistently during RT, first increased then decreased, increased consistently, first decreased then increased. Patients whose Kyn:Trp ratio kept decreasing or first increased then decreased were defined as good-change group. The good-change status was identified as an independent positive factor for overall survival (OS) and progression-free survival (PFS) (p=0.04; p=0.01) in multivariate analysis among evaluated parameters. Patients with good change showed significantly superior local control than bad-change group (p=0.01, HR=0.22). In 113 stage III NSCLC patients with pre-radiation Kyn:Trp ratio, a trend that high baseline IDO1 activity was associated with short OS was observed (p=0.079).</p><p><strong>CONCLUSION: </strong>Favorable change of IDO1 activity during RT was associated with superior OS, PFS and local control. IDO1 activity is a promising biomarker for prognosis in stage III NSCLC patients.</p>
2022-08-05 | MTBLS5267 | MetaboLights
Project description:Squamous cell lung carcinoma (SCC) corresponds to about 25% of all lung cancers. Therapeutic approaches are very limited and platinum-based chemotherapy remains the main treatment option. Despite multiple studies, there are no generally accepted predictive biomarkers for SCC. Transforming growth factor-β (TGFβ) signaling was shown to be implicated in numerous pro-tumorigenic processes, including immune evasion, inflammation and cancer metastasis. In the context of SCC epithelial-to-mesenchymal transition phenotype that is commonly mediated by TGFβ was widely observed in surgically resected specimens. However, the relation between TGFβ-induced changes and SCC progression remains to be elucidated. In the presented work, we combined phenotypic and transcriptome-wide approaches to identify novel predictive biomarkers for SCC. We show that TGFβ treatment activated Smad-mediated signal transduction and resulted in increase of migratory and invasive properties of SK-MES1 cells. Multiple actin cytoskeleton-related proteins, including myosin motor proteins such as Myosin-X, were up-regulated upon TGFβ stimulation. siRNA-mediated knockdown of Myosin-X completely abrogated TGFβ-induced collagen gel invasion. Finally, analysis of mRNA expression in paired surgically resected tissues of 151 SCC patients with corresponding 80-month clinical follow-up, showed that the mRNA expression ratio of Myosin-X in tumor and adjacent non-tumor tissue is predictive for overall survival and chemotherapy resistance independently of tumor stage. Given Myosin-X role in cellular motility and invasion, it can represent a new biomarker for aggressive disease and serve as a potential molecular target for therapeutic intervention in patients with SCC.
2018-06-15 | GSE95536 | GEO
Project description:Proteomics of transforming vs. non-transforming lichen planus.
2022-08-15 | MSV000090139 | MassIVE