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C. Kim

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    MS 12 - NSCLC Stems Cells: Are They a Real Target? (ID 30)

    • Event: WCLC 2015
    • Type: Mini Symposium
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      MS12.04 - Tumor-Propagating Cells in Non-Small Cell Lung Cancers (ID 1903)

      14:15 - 15:45  |  Author(s): C. Kim

      • Abstract
      • Presentation

      Our long-term goal is to elucidate the role of stem cells in lung homeostasis as a prerequisite to the development of therapeutic strategies that can be used to prevent or attenuate lung disease and lung cancer. Our previous experience isolating the first stem cell population from the adult murine lung, termedbronchioalveolar stem cells (BASCs), and our demonstration of a role for these cells in lung cancer serves as a platform to address these questions. We have recently developed three-dimensional co-culture and subcutaneous co-injection assays that allow us to quantitatively assess the identity and the differentiation potential of lung stem cells. This approach led us to uncover a cross-talk between lung endothelial cells and lung stem cells via a novel signaling axis involving Bmp4, NFATc1 and Tsp1;this pathway drives BASCs to differentiate into the alveolar epithelial cell lineage. Our work in the intersection of stem cell biology and lung disease has expanded into new insights for understanding metastasis and non-small cell lung cancer (NSCLC). We previously showed the adenocarcinoma Kras/p53 mutant mouse model contains Sca1+ tumor-propagating cells (TPCs), the cells that recapitulate the tumor by transplantation. We recently showed multiple lung tumor sub-populations can give rise to metastatic disease, and that the Sca1+ CD24+ TPCs have the highest metastatic potential. We also showed the Hippo pathway mediators Yap/Taz are necessary andsufficient for lung cancer progression. Finally, in a new mouse model of lung squamous cancer, the second most common type of NSCLC, we identified a TPC population defined by the markers Sca1 and NGFR. These studies illustrate the utility of stem cell biology approaches to provide new avenues for lung cancer therapeutic targeting.

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    P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      P1.04-059 - The Role of Histone Methyltransferases G9a/Glp in Mouse Lung Tumor Propagating Cells and Lung Stem Cells (ID 1543)

      09:30 - 17:00  |  Author(s): C. Kim

      • Abstract
      • Slides

      Proper epigenetic control of transcription is essential for stem cell homeostasis and is frequently disrupted in cancer, but this has not been well investigated in lung biology or lung disease. We have previously demonstrated that the stem cell marker Sca-1 enriches for mouse bronchioalveolar stem cells (BASCs) and lung adenocarcinoma cells with enhanced metastatic and tumor propagation abilities (TPCs).

      I performed a small chemical library screen using a Kras; p53-flox driven mouse lung adenocarcinoma cell line, CK1750 with high expression of the stem cell markers Sca-1 and CD24. Chemically treated cels were seperated and screened by FACS analysis for changes in the surface antigens Sca-1 and CD24. I treated Sca-1 low expressing mouse lung adenocarcinoma cell lines TM1 and TnM2 with either 1 uM UNC0638 or DMSO for 4 days. 100,000 cells per mouse were injected intravenously. After 3-4 Weeks mice were sacrificed and lungs and other organs were analyzed for tumor formation. Treated cells were also plated in 3D organoid culture and grown for 14 days. After this matrigel plugs were fixed and counted for organoid formation. I isolated BASCs and AT2 cells from 6 week old mice by FACS and plated cells in 3D organoid co-culture. Cells were grown with either 250 nM UNC0638 or DMSO for 21 days. At this point plugs were fixed, sectioned and organoids were stained for lung lineage markers SPC and CC10 and organoids expressing each were scored.

      A FACS screen of adenocarcinoma cell lines revealed that UNC0638, an inhibitor of H3K9me1/2 methyltransferases G9a and Glp enriches for high Sca-1 expressing, TPC-like cells. Gene expression analysis of primary adenocarcinomas shows that G9a/Glp are down-regulated in Sca-1+ metastatic TPCs. Furthermore, analysis of 400+ early stage patient lung adenocarcinomas reveals that low G9a expression and high expression of KDM3A, an H3K9me1/2 demethylase, significantly correlate with worse survival (P=0.008, P=0.002). This implies that dysregulation of H3K9me1/2 is also a significant factor in human disease. Interestingly, G9a/Glp inhibition of adenocarcinoma cells prior to transplantation increases Sca-1+ cells but does not increase recipient lung tumor burden. Instead, significantly more tumors are found in non-lung locations (58% vs. 13%, P=0.02). Whilst inhibition does not affect cell proliferation or migration, colony forming efficiency in 3D organoid culture is significantly increased (1.1% vs 0.3%, P=0.04). This suggests that altered stem-like properties such as tumor initiation may underlie the more tumorigenic phenotypes of H3K9me1/2 low, Sca-1+ TPCs. H3K9me1/2 also regulates the behavior of lung stem cells. G9a/Glp inhibition of BASCs or alveolar type 2 cells in 3D co-culture assays increases both Sca-1+ cells and undifferentiated organoids, and significantly decreases alveolar-lineage organoids (P<0.0005). BASC cultures also show increases in bronchiolar-lineage organoids (P<0.0005), implying that cell fate decisions may regulated by H3K9me1/2.

      These findings suggest that common mechanisms of epigenetic regulation exist between mouse lung stem cells and lung TPCs. Determining the precise mechanisms of this regulation will be important for our understanding of lung biology and disease, with potential implications for the diagnosis and treatment of human adenocarcinoma.

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