Author of

• 30723

  +

  P1.03 - Biology (ID 161)

  • Event: WCLC 2019
  • Type: Poster Viewing in the Exhibit Hall
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall

  • 30744

    +

    P1.03-21 - Epigenome-Wide Association Study of Cancer Associated Fibroblasts-Induced Oncogenic Transformation of Lung Epithelial Cells (ID 2602)

    09:45 - 18:00  |  Presenting Author(s): Sheng-Fang Su
    • Abstract

    Background
    

    Cancer-associated fibroblasts (CAFs) provide a microenvironment suitable for tumor development. CAFs have been shown to hold the capacity to facilitate carcinogenesis, drug resistance, tumor recurrence and metastasis through the signaling networks. Most studies investigating the impact of CAFs have focused on the cancer cells. The issue that how CAFs could induce carcinogenesis in the adjacent normal tissues, including genetic and epigenetic changes; however, attracts less attention. We aimed to characterize CAF-driven molecular changes in non-tumorous epithelial cells by genome/epigenome-wide study.

    Method
    

    We primary cultured CAFs from NSCLC patients and co-cultured CAFs with normal human epithelial cells (BEAS2B). We performed in vitro soft agar assay and processed the established cocultured clones onto the methylome and transcriptome high-throughput platforms.

    Result
    

    We found that the CAF-BEAS2B coculture could form colonieson the soft agar while CAFs or BEAS2B alone could not. Following isolation, the cells of cocultured clones developed more colonies than the parental BEAS2B by colony formation assay. The absence of CAF marker CD90 staining indicated no CAF contamination in the cocultured clones. In addition, DNA methylation profiling integrated with gene expression identified clusters (eg. ROBO1) that could discriminate cocultured clones from parental BEAS2B cells. The results of this study showed that CAFs could induce normal epithelial cells to undergo oncogenic transformation via DNA methylation regulation, suggesting the pro-tumorigenic potency of CAFs.

    Conclusion
    

    Exploring the molecular interaction between CAFs and surrounding normal cells could help clarify the role of CAFs predisposed in the microenvironment in transforming normal cells epigenetically.

• 30780

  +

  P2.03 - Biology (ID 162)

  • Event: WCLC 2019
  • Type: Poster Viewing in the Exhibit Hall
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall

  • 30821

    +

    P2.03-40 - Particle Matters Induce Carcinogenic Phenotype and Gene Expression Changes in Murine Pulmonary Progenitor Cells (ID 2143)

    10:15 - 18:15  |  Author(s): Sheng-Fang Su
    • Abstract

    Background
    

    The leading cause of cancer deaths points to lung cancer which tends to exacerbate, especially the cases of never-smokers in East Asian. While environmental exposure to air pollutants-particle matters (PMs) has been reported to increase the risk of lung cancer; the organic or inorganic chemicals absorbed in the surface of particles, including polycyclic aromatic hydrocarbons (PAHs), dioxins or other heavy metals are identified as carcinogens. However, the underlying mechanisms and the extent to which the toxicity of co-exposure to PMs and environmental carcinogens in pulmonary cells remain unclear.

    Method
    

    Here, we used a well-developed murine lung progenitor cell model with the cells primary cultured from neonatal mice and sorted as the OCT4+/CARHi sub-population to expose with fine PMs (urban dust) or ultrafine particles (nano-carbon black, nCB) with/without carcinogens (Benzo[a]pyrene, B[a]P and 2,3,7,8-Tetrachlorodibenzo-p-dioxin, TCDD). High content analysis (HCA) was applied to quantify the progenitor cell population and differentiated alveolar epithelial cells; and the cellular heterogeneity was also examined. The transcriptomics and gene enrichment analysis were also performed to explore the molecular mechanisms via the gene set enrichment analysis with the molecular signatures database.

    Result
    

    We found that co-stimulating the progenitor cells with TCDD and nCB can cause most significantly effects on activating cell proliferation, reducing cell differentiation and remarkably morphological diversity. The potential stemness sub-population of CAR-positive lung progenitor cells was increased following TCDD treatment and forming more significantly colony in the TCDD-nCB co-exposure group; whereas, the population of differentiated pulmonary lung epithelial cells was reduced. Transcriptomic analysis showed that the TCDD-induced genes: AHR, Cyp1A1, COX-2, and TCDD-inducible poly(ADP-ribose) polymerase are significantly up-regulated. The pathway analysis revealed important oncogenic transcriptional factors (TFs): STAT2, IRF1, AHR, BRCA1, and FOS are highly enriched and several key factors on EGFR, RAF, AKT, E2F1, MEK, and LTE2 were identified via the MSigDB oncogenic signatures. Furthermore, the co-exposure of TCDD with nCB also dysregulated the Wnt signaling pathway, cytokine networks (CCLs-CXCLs-CXCRs), antigen processing and presentation, IL-2 receptor signaling, interferon and TNF signaling that are critical on immune homeostasis in the microenvironment.

    Conclusion
    

    In conclusion, co-exposure of ultrafine particles with carcinogens could induce cell proliferation and suppress differentiation in mice lung progenitor cells; and lead to oncogenic and immune-modulatiing gene dysregulation. This study suggests the synergistic effects of the environmental carcinogens and PMs on the initiation of hyperplasia and malignant transformation of the lung progenitor cells via regulating gene expression related to oncogenic TFs, immunity and paracrine niche.