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A. Berns

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    PLEN 03 - Science Drives Lung Cancer Advances (ID 52)

    • Event: WCLC 2015
    • Type: Plenary
    • Track: Plenary
    • Presentations: 1
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      PLEN03.05 - Mouse Models of SCLC and NSCLC (ID 2047)

      08:15 - 09:45  |  Author(s): A. Berns

      • Abstract
      • Presentation

      Lung cancer and mesotheliomas belong to the most lethal human malignancies with poor prognosis. The majority of these tumors is associated with carcinogen exposure (smoking and asbestos). Small cell lung cancer (SCLC) and mesothelioma patients show very poor survival statistics due to their late detection, invasive and high metastatic potential, and chemo-resistance. Using the Rbf/f;p53f/f mouse model for SCLC, we found that the tumors are often composed of phenotypically different cells, characterized by mesenchymal and neuroendocrine markers. These cells often share a common origin. Crosstalk between these cells can endow the neuroendocrine component with metastatic capacity, illustrating the potential relevance of tumor cell heterogeneity in dictating functional tumor properties. Also specific genetic lesions appear to be associated with metastatic potential. We have studied the nature of this crosstalk and identified the components responsible for paracrine signaling and the downstream effector pathway critical for promoting metastatic spread. We have also evaluated the relevance of additional lesions that were frequently acquired in the mouse SCLC, such as amplification of Myc and Nfib. Therefore, we have derived ES cells from Rbf/f;p53f/f, equipped these cells with an exchange cassette in the ColA1 locus, and shuttled a conditional L-Myc and Nfib under a strong promoter into this locus. This accelerated tumorigenesis and resulted also in a shift in the metastatic phenotype. To investigate the cell-of-origin of thoracic tumors, we have inactivated a number of tumor suppressor/oncogene combinations (Trp53, Rb1, Nf2, Cdkn2ab-p19Arf, mutant Kras) in distinct cell types by targeting Cre-recombinase expression specifically to Clara cells, to neuroendocrine cells, alveolar type II cells and cells of the mesothelial lining (origin of malignant mesothelioma) using adenoviral or lentiviral vectors with Cre recombinase driven from specific promoters. Dependent on the induced lesions and the cell-type specific targeting, SCLC, NSCLC, or mesothelioma could be induced. We show that multiple cell types can give rise to these tumors but that the cell-of-origin is an important factor in determining tumor phenotype. Our data indicate that both cell type specific features and the nature of the oncogenic lesion(s) are critical factors in determining the tumor initiating capacity of lung (progenitor) cells. Furthermore, the cell-of-origin appears to influence the malignant properties of the resulting tumors. Sutherland, K., Song, J-Y., Kwon, M-C, Prooost and Berns A. (2014). Multiple cells-of-origin in K-RasG12D induced mous lung adenocarcinoma. Proc. Natl. Acad. SCi. USA, 111, 4952-4957. Kwon, M-C, and Berns, A. (2013) mouse models of Lung Cancer. Mol. Oncol. 7, 65-177. Sutherland, K.D., Proost, N., Brouns, I., Adriaensen, D., Song, J-Y., and Berns, A. (2011). Cell of Origin of Small Cell Lung Cancer: Inactivation of Trp53 and Rb1 in Distinct Cell Types of Adult Mouse Lung. Cancer Cell 19, 754-64. Calbo, J., van Montfort, E., Proost, N., van Drunen, E., Beverloo, H., Meuwissen, R., and Berns, A. (2011) A functional role for tumor cell heterogeneity in a mouse model of Small Cell Lung Cancer. Cancer Cell, 19, 244-56.

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