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M. Tissari



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    OA02 - Novel Targets and Biomarkers in Malignant Pleural Mesothelioma (ID 369)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
    • Presentations: 1
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      OA02.02 - Gremlin-1 is a Key Regulator of the Invasive Phenotype in Mesothelioma (ID 5424)

      11:00 - 12:30  |  Author(s): M. Tissari

      • Abstract
      • Presentation
      • Slides

      Background:
      Malignant mesothelioma is an aggressive cancer that develops from mesothelial cells, most often in the pleural lining of the lung. We have previously shown that the BMP inhibitor protein gremlin-1 is highly expressed in mesothelioma and induces a mesenchymal and chemoresistant phenotype in mesothelioma cells. Since mesothelioma tumors are locally highly invasive, we analyzed the role of gremlin-1 in mesothelioma cell migration and invasive growth.

      Methods:
      Primary mesothelioma cells isolated from patient pleural fluid as well as mesothelioma cell lines were used for in vitro studies. Cells were transfected with siRNAs or transduced with lentiviral expression vectors. Invasive growth was analyzed in 3D matrigel or collagen I matrices. mRNA expression was analyzed using a commercial PCR array and quantitative RT-PCR. Migration assays were performed using scratch wound assay or Transwell migration assay with fibronectin or collagen coating. TGF-β and BMP signaling activity was measured with reporter-luciferase assays. For in vivo mouse xenograft experiment cells were additionally transduced to express a luciferase marker. Subcutaneous cell injection with matrigel matrix was performed in the flank of nude mice.

      Results:
      Mesothelioma cells expressing gremlin-1 showed invasive sprouting when tumor cell spheroids were imbedded into 3D collagen matrix. Silencing of gremlin-1 expression significantly reduced invasive growth. In addition, cells overexpressing gremlin-1 gained invasive growth ability. This was associated with increased mRNA expression levels of Slug and matrix metalloproteinases (MMP) as well as reduced expression of E-cadherin. The cells were more migratory and exhibited increased expression of certain integrins, especially the α~v~ subunit. Gremlin-1 induced invasive growth was dependent on MMP activity and associated with increased TGF-β activity. Intrapleural injection of gremlin-1 overexpressing mesothelioma cells isolated from a patient with epithelioid mesothelioma, produced tumors in 2/4 mice over 4 months after injection. Cells transduced with vector only did not produced tumors (0/4). When cells were injected subcutaneously together with matrigel gremlin-1 overexpressing tumors appeared more slowly, but exhibited comparable luciferase signal 2.5 months after injection. However, gremlin-1 tumors showed more local spreading and in contrast to control tumors some also developed metastasis (2/6 mice).

      Conclusion:
      Mesothelioma invades locally and has poor prognosis. We have identified gremlin-1 as an important regulator of mesothelioma chemoresistance and invasive growth behavior. Blocking gremlin function may overcome drug resistance and reduce invasion of mesothelioma.

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