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C. Pastrello



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    P2.01 - Poster Session with Presenters Present (ID 461)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Biology/Pathology
    • Presentations: 2
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      P2.01-024 - Expression of miR-106 Paralogs Improves Prognostic Value of Mesenchymal Signatures but Only miR-106b Promotes Invasiveness (ID 6250)

      14:30 - 14:30  |  Author(s): C. Pastrello

      • Abstract

      Background:
      Improved understanding of the molecular mechanisms driving lung cancer progression can lead to novel therapeutic strategies to improve the currently poor patient treatment outcome. Deregulation of microRNA (miRNA) expression in malignant cells activates molecular pathways that drive tumor progression such as epithelial-mesenchymal transition (EMT). We identify miRNA paralogs, miR-106a and miR-106b, to be elevated in metastatic lung adenocarcinoma (LUAD). We assess whether these two highly similar miRNAs share the same functions in vitro, and measure how their elevated expression increases invasiveness or induces EMT in LUAD tumor.

      Methods:
      MiRNA expression was obtained from small RNA sequencing data derived from clinical primary LUAD specimens and paired non-malignant tissues (60 localized, 27 with lymph node invasion). Non-invasive, epithelial LUAD cell lines with low endogenous miR-106a/b levels were transfected and co-transfected with overexpression vectors for miR-106a and miR-106b. Invasiveness of experimentally-modulated tumor cells was assessed in vitro by Boyden chamber assay and in vivo using a zebrafish model, and expression of EMT markers was determined by Western Blot. Predicted miRNA targets were identified using mirDIP portal. To identify putative genetic mechanisms of mir-106a/b overexpression, DNA copy number, methylation, and Gene Set Enrichment Analysis (GSEA) were performed. Clinical associations were computed in an independent cohort of TCGA LUAD samples.

      Results:
      Both miR-106 paralogs were significantly overexpressed in LUAD samples with lymph node invasion. However, increased expression of miR-106b alone or together with miR-106a, but not miR-106a alone, enhanced metastatic phenotypes, and correlated with increased mesenchymal and decreased epithelial marker expression. Predicted targets include EP300, a transcriptional activator of E-cadherin, and members of the TGFβ signaling pathway. Copy number and methylation status did not correlate with miRNA expression; however, GSEA analysis revealed enrichment of E2F transcription factor targets in LUAD with high expression of either miR-106 paralogs. Furthermore, expression of miR-106 paralogs was significantly positively correlated with E2F1 and E2F2, suggesting that upstream regulation by E2F is a potential mechanism. Interestingly, miR-106a and miR-106b expression was associated with poor survival and advanced stage when stratified by mesenchymal marker vimentin.

      Conclusion:
      Although both miR-106a and miR-106b are overexpressed in metastatic LUAD, the strongest prognostic association was found in LUAD with a mesenchymal expression signature and high expression of both miRNAs. Our cell models suggest that miR-106b may play a direct role in EMT, with miR-106a influencing tumor progression via alternative mechanisms. Inhibition of one or both of these miRNAs may provide a strategy for treating advanced stage disease.

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      P2.01-037 - Molecular Biology Underlying COPD and Lung Cancer Converge on FOXM1 Network (ID 5773)

      14:30 - 14:30  |  Author(s): C. Pastrello

      • Abstract

      Background:
      Chronic obstructive pulmonary disease (COPD) is a progressive, inflammatory lung disease associated with an up to 10-fold increased risk of lung cancer (LC). COPD and LC share common etiologies including genetic susceptibilities and risk factors, such as smoking. This study systematically characterizes the molecular overlap between COPD and LC.

      Methods:
      Small airway gene expression data was obtained from subjects with spirometry measures (n=267) (GSE37147). Genome-wide, multi-omics data for lung adenocarcinoma (LUAD) tumor and non-malignant lung tissues from two cohorts (TCGA, n=515; BCCA, n=90) was analyzed. Weighted correlation network analysis (WGCNA) was applied to identify clusters (modules) of highly correlated genes across airway expression profiles. Combined module expression (eigengene scores) were used to: 1) identify modules negatively associated with FEV~1~ and 2) calculate module preservation in lung tumors. Signaling network, pathway and gene ontology analyses were performed using IID, pathDIP, ClueGo and PARADIGM. Known and predicted protein-protein physical interactions (PPIs) were obtained from IID. Network analysis and visualization was performed in NAViGaTOR.

      Results:
      A module of 31 genes significantly co-expressed across small airways was negatively associated with FEV~1~ and preserved in LUAD tumors. Genes in this module were enriched in functions associated with cell cycle progression, and known and/or predicted to physically interact in the protein complex critical to mediating G2/M progression. The forkhead transcription factor FOXM1 network was the most highly perturbed entity across 515 LUAD tumors. FOXM1 is an essential mitotic protein, known to regulate expression of genes involved in cell cycle progression, as well as stress response to ROS and DNA damage, angiogenesis and metastasis. COPD-related airway mRNA changes and genes highly altered at the DNA and mRNA level in LUAD tumors directly converge on the FOXM1 regulated mitotic complex proteins and/or FOXM1 transcription factor network.

      Conclusion:
      FOXM1 is overexpressed in multiple cancer types where it is correlated with poor prognosis and oncogenic transformation of epithelia through induction of genomic instability. The convergence of COPD and LUAD changes on this network may underlie increased LC risk in COPD patients, warranting further exploration as a target for COPD treatment and/or LC prevention or treatment.

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    P3.01 - Poster Session with Presenters Present (ID 469)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P3.01-051 - Analysis of Molecular Aberrations Associated with COPD in Patients with Lung Cancer (ID 5220)

      14:30 - 14:30  |  Author(s): C. Pastrello

      • Abstract

      Background:
      Chronic obstructive pulmonary disease (COPD) is serious lung disease that is often associated with development of lung cancer. It is well known that both diseases share many common risk factors, most prominently smoking. Much less is known about molecular link between these two pathologies. How to predict which COPD patients will develop lung cancer? Can COPD drugs reduce or increase lung cancer risk?

      Methods:
      To answer these question we analyzed molecular data from tumour and normal tissue samples obtained from 72 lung cancer patients, comprising methylation, copy number aberrations, gene expression and microRNA expression data acquired from each sample. Various matching spirometric parameters, were used as indicator of severity of the airflow limitation in patients with COPD and were evaluated as potential prognostic indicators with respect to survival. We studied molecular aberrations to identify those that correlate with these parameters or differ between COPD and non-COPD patients. Using data from Broad Institute's Connectivity Map (CMAP), we analyzed gene expression effects of various pharmacological compounds, to identify potential benefits/hazards in administration of various drugs (and their combinations) typically used for treatment of COPD and/or lung cancer, with respect to prognosis of patients with COPD vs. those without COPD.

      Results:
      We identified group of 619 genes and 20 microRNAs whose expression is significantly associated with patient's COPD status (and severity of the disease). COPD-associated genes significantly enrich pathways related to G2 M phase of the cell cycle, G-protein coupled receptors signalling, Rho GTPases signalling and several cancer-related pathways. We found that subset of these genes constitute prognostic signature that was subsequently validated using independent publicly available dataset (HR = 2.66, p = 0.01, N = 204, GSE31210). We have also shown that alternative signature with similar prognostic power can also be constituted by COPD-associated micoRNAs (HR = 2.07, p = 0.036, N = 189, TCGA LUAD miRNAseq data). By subsequent CMAP analysis we then identified drugs that significantly (p < 0.01) affect expression of the COPD-associated genes in a manner that may improve the patients prognosis, and those that may cause its worsening. First mentioned include fenspiride – drug for obstructive airways disease and urological anti-infective phenazopyridine. Interestingly, we found calcium folinate - frequently used as a detoxifying agent for antineoplastic treatment, including treatment of lung cancer, as a potentially harmfull.

      Conclusion:
      Genes and microRNAs associated with COPD are significantly associated with prognosis of the lung cancer patients.