Dataset Information

Epithelial-mesenchymal transition (EMT) signature is inversely associated with T-cell infiltration in non-small cell lung cancer (NSCLC).

ABSTRACT: Epithelial-mesenchymal transition (EMT) is able to drive metastasis during progression of multiple cancer types, including non-small cell lung cancer (NSCLC). As resistance to immunotherapy has been associated with EMT and immune exclusion in melanoma, it is important to understand alterations to T-cell infiltration and the tumor microenvironment during EMT in lung adenocarcinoma and squamous cell carcinoma. We conducted an integrated analysis of the immune landscape in NSCLCs through EMT scores derived from a previously established 16 gene signature of canonical EMT markers. EMT was associated with exclusion of immune cells critical in the immune response to cancer, with significantly lower infiltration of CD4 T-cells in lung adenocarcinoma and CD4/CD8 T-cells in squamous cell carcinoma. EMT was also associated with increased expression of multiple immunosuppressive cytokines, including IL-10 and TGF-?. Furthermore, overexpression of targetable immune checkpoints, such as CTLA-4 and TIM-3 were associated with EMT in both NSCLCs. An association may exist between immune exclusion and EMT in NSCLC. Further investigation is merited as its mechanism is not completely understood and a better understanding of this association could lead to the development of biomarkers that could accurately predict response to immunotherapy.

SUBMITTER: Chae YK

PROVIDER: S-EPMC5811447 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Epithelial-mesenchymal transition (EMT) signature is inversely associated with T-cell infiltration in non-small cell lung cancer (NSCLC).

Chae Young Kwang YK Chang Sangmin S Ko Taeyeong T Anker Jonathan J Agte Sarita S Iams Wade W Choi Wooyoung M WM Lee Kyoungmin K Cruz Marcelo M

Scientific reports 20180213 1

Epithelial-mesenchymal transition (EMT) is able to drive metastasis during progression of multiple cancer types, including non-small cell lung cancer (NSCLC). As resistance to immunotherapy has been associated with EMT and immune exclusion in melanoma, it is important to understand alterations to T-cell infiltration and the tumor microenvironment during EMT in lung adenocarcinoma and squamous cell carcinoma. We conducted an integrated analysis of the immune landscape in NSCLCs through EMT scores ...[more]

PMID: 29440769

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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.

Project description:BackgroundPrevious studies have reported the role of circular RNAs (circRNAs) in the progression of non-small-cell lung cancer (NSCLC). SWT1-derived circRNAs were confirmed to affect the apoptosis of cardiomyocytes; however, the biological functions of SWT1-derived circRNAs in cancers are still unknown. Here, we investigated the potential role of SWT1-derived circRNAs in NSCLC.MethodsWe used quantitative real-time polymerase chain reaction (qRT-PCR) to measure the expression of circSWT1 in NSCLC tissues and paired normal tissues. The potential functions of circSWT1 in tumor progression were assessed by CCK-8, colony formation, wound healing, and matrigel transwell assays in vitro and by xenograft tumor models in vivo. Next, epithelial-mesenchymal transition (EMT) was evaluated by western blotting, immunofluorescence, and immunohistochemistry (IHC). Moreover, circRIP, RNA pulldown assays, luciferase reporter gene assays, and FISH were conducted to illuminate the molecular mechanisms of circSWT1 via the miR-370-3p/SNAIL signal pathway. Then, we knocked out SNAIL in A549 and H1299 cells to identify the roles of circSWT1 in the progression and EMT of NSCLC through SNAIL. Finally, circSWT1 functions were confirmed in vivo using xenograft tumor models.ResultsCircSWT1 expression was significantly upregulated in NSCLC tissues, and high expression of circSWT1 predicted poor prognosis in NSCLC via survival analysis. In addition, overexpression of circSWT1 promoted the invasion and migration of NSCLC cells. Subsequently, we found that overexpression of circSWT1 induced EMT and that knockdown of circSWT1 inhibited EMT in NSCLC cells. Mechanistically, circSWT1 relieved the inhibition of downstream SNAIL by sponging miR-370-3p. Moreover, we found that these effects could be reversed by knocking out SNAIL. Finally, we verified that circSWT1 promoted NSCLC progression and EMT in xenograft tumor models.ConclusionCircSWT1 promoted the invasion, migration, and EMT of NSCLC. CircSWT1 could serve as a potential biomarker and a potential therapeutic target for NSCLC.

Dataset Information

Epithelial-mesenchymal transition (EMT) signature is inversely associated with T-cell infiltration in non-small cell lung cancer (NSCLC).

Publications

Epithelial-mesenchymal transition (EMT) signature is inversely associated with T-cell infiltration in non-small cell lung cancer (NSCLC).

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