Dataset Information

Lymphangioleiomyomatosis Biomarkers Linked to Lung Metastatic Potential and Cell Stemness.

ABSTRACT: Lymphangioleiomyomatosis (LAM) is a rare lung-metastasizing neoplasm caused by the proliferation of smooth muscle-like cells that commonly carry loss-of-function mutations in either the tuberous sclerosis complex 1 or 2 (TSC1 or TSC2) genes. While allosteric inhibition of the mechanistic target of rapamycin (mTOR) has shown substantial clinical benefit, complementary therapies are required to improve response and/or to treat specific patients. However, there is a lack of LAM biomarkers that could potentially be used to monitor the disease and to develop other targeted therapies. We hypothesized that the mediators of cancer metastasis to lung, particularly in breast cancer, also play a relevant role in LAM. Analyses across independent breast cancer datasets revealed associations between low TSC1/2 expression, altered mTOR complex 1 (mTORC1) pathway signaling, and metastasis to lung. Subsequently, immunohistochemical analyses of 23 LAM lesions revealed positivity in all cases for the lung metastasis mediators fascin 1 (FSCN1) and inhibitor of DNA binding 1 (ID1). Moreover, assessment of breast cancer stem or luminal progenitor cell biomarkers showed positivity in most LAM tissue for the aldehyde dehydrogenase 1 (ALDH1), integrin-ß3 (ITGB3/CD61), and/or the sex-determining region Y-box 9 (SOX9) proteins. The immunohistochemical analyses also provided evidence of heterogeneity between and within LAM cases. The analysis of Tsc2-deficient cells revealed relative over-expression of FSCN1 and ID1; however, Tsc2-deficient cells did not show higher sensitivity to ID1-based cancer inhibitors. Collectively, the results of this study reveal novel LAM biomarkers linked to breast cancer metastasis to lung and to cell stemness, which in turn might guide the assessment of additional or complementary therapeutic opportunities for LAM.

SUBMITTER: Ruiz de Garibay G

PROVIDER: S-EPMC4500593 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Lymphangioleiomyomatosis Biomarkers Linked to Lung Metastatic Potential and Cell Stemness.

Ruiz de Garibay Gorka G Herranz Carmen C Llorente Alicia A Boni Jacopo J Serra-Musach Jordi J Mateo Francesca F Aguilar Helena H Gómez-Baldó Laia L Petit Anna A Vidal August A Climent Fina F Hernández-Losa Javier J Cordero Álex Á González-Suárez Eva E Sánchez-Mut José Vicente JV Esteller Manel M Llatjós Roger R Varela Mar M López José Ignacio JI García Nadia N Extremera Ana I AI Gumà Anna A Ortega Raúl R Plà María Jesús MJ Fernández Adela A Pernas Sònia S Falo Catalina C Morilla Idoia I Campos Miriam M Gil Miguel M Román Antonio A Molina-Molina María M Ussetti Piedad P Laporta Rosalía R Valenzuela Claudia C Ancochea Julio J Xaubet Antoni A Casanova Álvaro Á Pujana Miguel Angel MA

PloS one 20150713 7

Lymphangioleiomyomatosis (LAM) is a rare lung-metastasizing neoplasm caused by the proliferation of smooth muscle-like cells that commonly carry loss-of-function mutations in either the tuberous sclerosis complex 1 or 2 (TSC1 or TSC2) genes. While allosteric inhibition of the mechanistic target of rapamycin (mTOR) has shown substantial clinical benefit, complementary therapies are required to improve response and/or to treat specific patients. However, there is a lack of LAM biomarkers that coul ...[more]

PMID: 26167915

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Project description:Objective Cancer stemness and M2 macrophages are intimately linked to the prognosis of lung adenocarcinoma (LUAD). For this reason, this investigation sought to identify the key genes relevant to cancer stemness and M2 macrophages, explore the relationship between these genes and clinical characteristics, and determine the potential mechanism. Methods LUAD transcriptomic data was analyzed from The Cancer Genome Atlas (TCGA) as well as the Gene Expression Omnibus databases. Differential expression analysis was performed to discern abnormally expressed genes between LUAD and control samples in TCGA cohort. The Cell type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) algorithm was applied to determine varyingly infiltrated immune cells in LUAD compared with the control samples in TCGA cohort. Weighted correlation network analysis (WGCNA) was performed to identify genes associated with mRNA expression-based stemness index (mRNAsi) and M2 macrophages. Least absolute shrinkage and selection operator (LASSO), RandomForest (RF) and support vector machine-recursive feature elimination (SVM-RFE) machine learning methods were conducted to detect gene signatures. Global survival evaluation (Kaplan-Meier curve) was applied to investigate the relationship between gene signatures and the survival time of LUAD patients. Receiver operating characteristic (ROC) curves were produced to define biomarkers relevant to diagnosis. Gene Set Enrichment Analysis (GSEA) was performed to probe the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways related to diagnostic biomarkers. The public single-cell dataset of LUAD (GSE123902) was used to investigate the expression differences of diagnostic biomarkers in various cell types in LUAD. Real-time quantitative PCR (qRT-PCR) was performed to confirm key genes in lung adenocarcinoma cells. Results A total of 5,410 differentialy expressed genes (DEGs) as well as 15 differentially infiltrated immune cells were identified between LUAD and control sepcimens in TCGA cohort. Thirty-seven DEGs were associated with both M2 macrophages and mRNAsi according to the WGCNA analysis. Sixteen common gene signatures were obtained using three diverse algorithms. CBFA2T3, DENND3 and FCAMR were correlated to overall and disease-free survival of LUAD patients. ROC curves revealed that CBFA2T3 and DENND3 expression accurately classified LUAD and control samples. The results of single cell related analysis showed that two diagnostic biomarkers expressions were differed between the different tissue sources in M2-like macrophages. QRT-PCR demonstrated the mRNA expressions of CBFA2T3 and DENND3 were upregulated in lung adenocarcinoma cells A549 and H2122. Conclusion Our study identified CBFA2T3 and DENND3 as key genes associated with mRNAsi and M2 macrophages in LUAD and investigated the potential molecular mechanisms underlying this relationship.

Dataset Information

Lymphangioleiomyomatosis Biomarkers Linked to Lung Metastatic Potential and Cell Stemness.

Publications

Lymphangioleiomyomatosis Biomarkers Linked to Lung Metastatic Potential and Cell Stemness.

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