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S. Jayasekara



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    MO15 - Novel Genes and Pathways (ID 89)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO15.04 - Loss of Tumor Suppressor Hic1 Accelerates the Progression of Lung Adenocarcinoma Induced by Oncogenic KRas (ID 2655)

      16:30 - 16:35  |  Author(s): S. Jayasekara

      • Abstract
      • Presentation
      • Slides

      Background
      Hypermethylated in Cancer-1 (Hic1) is a novel tumour suppressor gene that is frequently epigenetically silenced in adult tumours. In non-small cell lung cancer (NSCLC), loss of Hic1 expression is associated with reduced patient survival, suggesting reduced Hic1 expression is associated with malignant progression of NSCLC. However, whether Hic1 silencing is causal in lung cancer is not known. Hic1 is a transcriptional repressor that can regulate p53 function by repressing the expression of SIRT1, a class III histone deacetylase. We therefore hypothesized that loss of Hic1 function could cooperate with an oncogenic mutation in KRas (KRasG12D) to promote lung cancer initiation and/or progression in a similar fashion to genetic deletion of p53.

      Methods
      To address this question, we used a conditional genetic mouse model of lung adenocarcinoma in which administration of recombinant adenovirus expressing Cre can trigger recombination at loxP sites. When virus is administered to mice heterozygous for a conditional KRasG12D allele, mice develop multiple lung adenomas that progress to adenocarcinomas over 8-12 weeks. To test the function of Hic1 as a tumour suppressor, we created a conditional knockout mouse allele (Hic1[lox]), in which loxP sites flank the single coding exon.

      Results
      Following administration of Cre adenovirus, mice carrying the KRasG12D allele and homozygous for the Hic1[lox] allele, developed aggressive lung adenocarcinomas at a markedly accelerated rate and had a significantly shortened survival compared to KRasG12D animals. Remarkably, these tumours exhibited a highly malignant phenotype with highly proliferative micropapillary and pleomorphic features.

      Conclusion
      These data show that loss of Hic1 function can substitute for p53 mutation as a cooperating event in lung adenocarcinoma progression. Since the highly aggressive phenotype of KRasG12D/Hic1[lox/lox] lung tumours has not been reported in the KRasG12D/p53[lox/lox] lung cancer model, we speculate that Hic1 may function as a tumour suppressor beyond the regulation of p53 through Sirt1.

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    P1.05 - Poster Session 1 - Preclinical Models of Therapeutics/Imaging (ID 156)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.05-009 - Development of small cell lung cancer primary xenografts using specimens obtained by endobronchial-ultrasound transbronchial needle aspiration: a novel pre-clinical model (ID 1549)

      09:30 - 09:30  |  Author(s): S. Jayasekara

      • Abstract

      Background
      Lung cancer has the highest cancer incidence and mortality worldwide. Small cell lung cancer (SCLC) accounts for 15% of all cases. Platinum-based chemotherapy induces responses in up to 70%. However, treatment-resistant recurrence is near universal, and 5-year survival remains poor at 1-2%. Therefore, there is urgent need for pre-clinical models that accurately recapitulate the parent tumour and allow testing for predictive biomarkers of response and resistance to drugs, and also screening of novel anticancer agents. Furthermore, as the vast majority of SCLC are inoperable, it is crucial that the mode of tumour tissue acquisition be minimally invasive and repeatable in cases of recurrence. Here we describe a novel pre-clinical model using samples obtained by the minimally invasive technique of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) to develop primary xenografts of SCLC.

      Methods
      Cell suspensions from samples of SCLC obtained by EBUS-TBNA were implanted directly into the flanks of NSG (Non-Obese Diabetic, Severe Combined Immune Deficient, IL2Rγ knockout) mice to generate primary xenografts. The mice were monitored for tumour growth, and if engraftment was successful, pre-graft and post-graft tumours were compared in terms of morphology, immunohistochemistry and molecular characteristics.

      Results
      Thus far, 14 SCLC specimens have been implanted, with 7 cases completing 6 months of tumour monitoring. Of these, 6 have undergone successful engraftment (86%). Samples typically contained over 1 million tumour cells with minimal stromal contamination. Mean engraftment lag time was 96 days. In all cases of engraftment, histological and molecular fidelity to the original tumour was demonstrated.

      Conclusion
      This is the first report of the generation of a primary xenograft model of lung cancer using a new method of tissue acquisition by EBUS-TBNA. Furthermore, it is the largest reported group of primary xenografts of SCLC. The primary xenograft lines from these specimens may provide the much-needed basis for more accurate pre-clinical modeling of SCLC, and hold great translational promise for novel therapeutic agents.