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Kwon-Sik Park



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    MS 26 - Re-Modeling Microenvironment Mimicking Human Cancer (ID 548)

    • Event: WCLC 2017
    • Type: Mini Symposium
    • Track: Biology/Pathology
    • Presentations: 1
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      MS 26.05 - In Vitro Model of Early Progression in SCLC (ID 7768)

      15:50 - 16:10  |  Presenting Author(s): Kwon-Sik Park

      • Abstract
      • Presentation
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      Abstract:
      The abundance of somatic alterations and their heterogeneity between SCLC patient tumors present the immense scientific and clinical challenges. Functional characterization of recurrent mutations in SCLC is an essential step towards understanding the pathogenesis. However, it remains extremely difficult due to the lack of systematic and informed ways of defining oncogenic drivers, especially those involved in early stage tumor development. While the inaccessibility of precancerous lesion in the patients has precluded characterization of lung cancer mutations, we have developed a precancerous cell-based model of SCLC development as a streamlined approach for characterizing novel mutations and determining mutation-driven oncogenic pathways [Kim et al. 2016, Genes and Development]. Using compound transgenic mice expressing neuroendocrine specific GFP in the GEMM of SCLC (Chga-GFP/Rb/p53/Rbl2), we isolated pulmonary neuroendocrine cells one month after adenoviral Cre-mediated tumor induction, at which time the lungs did not show macroscopic lesions (Figure 1). Notably, these cells from an early stage of tumor development grew as adherent monolayers in culture and did not form subcutaneous tumors in nude mice, whereas tumor cells formed floating aggregates and formed the subcutaneous tumors. These findings indicated that these neuroendocrine cells, lacking Rb and p53, were immortalized but not transformed. Therefore, we postulated that these cells were precancerous cells of SCLC (preSC). We then tested whether preSC could be transformed by an oncogene, using a retroviral vector carrying cDNA of L-Myc, one of the most frequently amplified genes in SCLC. The preSC transduced with retroviral L-Myc (L-Myc-preSC) formed spheres characteristic of SCLC cells in culture and palpable tumors resemble primary SCLC in the flanks of nude mice, whereas GFP-preSCs (control) were morphologically identical to uninfected preSC and did not form aggregates and subcutaneous tumor (Figure 2A). Comparative expression profiling of preSCs and L-Myc-preSC or tumor cells permitted identification of the genes and pathways related to oncogene-driven tumor progression. Defining the MYC-driven oncogenic pathways led to a preclinical test of an existing drug that successfully targeted human and mouse SCLC tumors. Furthermore, using this preSC-based model in combination with CRISPR/Cas9 methods of gene targeting and in vivo models, we found that several loss-of-function mutations found in the SCLC tumors were sufficient to cause the tumorigenic progression of preSCs (Figure 2B). In conclusion, this engineered preSC-based model facilitates functional validation of the recurrent mutations in SCLC and discovery of biomarkers and molecular pathways that will be further explored for mechanistic elucidation and targeted therapies.Figure 1



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