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JEREMY JW Chen



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    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
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      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): JEREMY JW Chen

      • 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.