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B. Gomperts

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    MS 25 - Lung Carcinogenesis (ID 43)

    • Event: WCLC 2015
    • Type: Mini Symposium
    • Track: Screening and Early Detection
    • Presentations: 1
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      MS25.02 - Transcriptional Profiling of Malignant Lesions (ID 1959)

      14:15 - 15:45  |  Author(s): B. Gomperts

      • Abstract
      • Presentation

      Epithelial cancers are thought to arise in a stepwise fashion from premalignant lesions and removal of premalignant lesions in epithelia such as colon and cervix has made a major improvement in survival in these cancers. However, premalignant lesions of the airway epithelium are poorly understood and it is not even known whether they represent a true premalignant state. This is in large part because of the heterogeneity of premalignant lesions of the airway and the fact that most of them will spontaneously resolve, even in high-risk patients. Premalignant lesions are thought to arise because of aberrant repair after injury but our understanding of the biology of normal repair after injury of the airways is limited and thus we do not know what the mechanisms are that drive aberrant repair and even less what the mechanisms are that drive the development of invasive non-small cell lung cancer. In order to increase our understanding of premalignant lesions of the airway, we laser-microdissected representative cell populations along the purported squamous cell lung cancer pathological continuum of patient-matched normal basal cells, premalignant lesions, and tumor cells. We obtained sufficient mRNA to perform high throughput RNA-sequencing. We discovered transcriptomic changes and identified genomic pathways altered with initiation and progression of SCC within individual patients. We used immunofluorescent staining to confirm gene expression changes in premalignant lesions and tumor cells, including increased expression of SLC2A1, CEACAM5, and PTBP3 at the protein level and increased activation of MYC via nuclear translocation. Cytoband enrichment analysis revealed coordinated loss and gain of expression in chromosome 3p and 3q regions, respectively, during carcinogenesis. We also identified several pathways that were upregulated in a stepwise fashion with progression of lesions. One of the pathways found to be upregulated with stepwise progression was redox regulation. Low levels of Reactive Oxygen Species (ROS) are known to be critical for cell regulation, while high levels of ROS are toxic to cells. We found that airway basal stem cells have low levels of ROS at baseline, but injury results in an increase in ROS and this flux from low to higher levels of ROS mediates proliferation of the basal cells via signaling through ROS/Nrf2/Notch1. Perturbation of this pathway at the level of Nrf2 or Notch both in vitro and in vivo results in excessive proliferation of basal cells and the formation of premalignant lesions with hyperplasia and dysplasia of the repairing airway epithelium. Our results provide much needed information about the biology of airway epithelial repair, premalignant lesions and the molecular changes that occur during stepwise carcinogenesis of squamous cell lung cancer, and it highlights a novel approach for identifying some of the earliest molecular changes associated with initiation and progression of lung carcinogenesis within individual patients.

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