Author of

• 18606

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  P3.03 - Poster Session with Presenters Present (ID 473)

  • Event: WCLC 2016
  • Type: Poster Presenters Present
  • Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
  • Presentations: 1
  • Moderators:
  • Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)

  • 18620

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    P3.03-014 - Tumor Subtype-Specific Cells-Of-Origin of Malignant Pleural Mesothelioma (ID 5078)

    14:30 - 14:30  |  Author(s): I. De Rink
    • Abstract

    Background:
    Malignant pleural Mesothelioma (MPM) belongs to the most deadly cancers and is closely associated with asbestos exposure. Tumors arise typically after a long latency period (20-50 years) and three different tumor subtypes have been identified: epithelial, sarcomatoid and biphasic. Chirurgical resection can expand lifespan but is not curative and unfortunately, no effective chemotherapy or targeted therapies are currently available to effectively treat MPM. A better understanding of the molecular basis of the disease is urgently needed and therefore we have assessed what the cells-of-origin are in MPM using a versatile in vivo – in vitro system and how this influences tumor characteristics.
    
    Methods:
    Primary mesothelial cells isolated from Cdkn2a deficient mice carrying conditional alleles of Nf2 and Trp53 were transduced in vitro by lentiviruses expressing Cre-recombinase driven from a general promoter. After culturing these cells for a few passages to maintain the cellular heterogeneity, clonal cell lines were selected and analysed for their protein expression marker profile related to subtype-specific expression of markers used for MPM diagnosis. Histopathological analysis of MPM tumors that developed in recipient mice after grafting of primary cell populations and clonal cell lines was performed as well as the effect of the extra-cellular matrix (ECM) on the differentiation of the target cell for transformation in vitro. RNAseq profiles of our mice derived cell lines were compared to a large data set of human primary MPMs.
    
    Results:
    Transplantation of recombined primary mesothelial cell populations in immuun proficient recipient mice resulted in efficient MPM development of all tumor subtypes. Clonal sarcomatoid cells accelerated tumor development significantly compared to clonal epithelial clonal cells after grafting and both cell types retain their phenotype during tumorigenesis. Clonal biphasic cells are less tumorigenic and require an immuun deficient background to develop into biphasic tumors with varying contributions of epithelial and sarcomatoid tumor cells. In vitro we show that biphasic cell differentiation (into either epithelial or sarcomatoid tumor cells) is jointly regulated by the composition and stiffness of the cellular matrix. RNAseq performed on tumor subtype-specific clonal cell lines shows that epithelial cells are highly similar to biphasic cells while sarcomatoid cells show a different profile.
    
    Conclusion:
    Our results indicate that multiple cell-types sharing the same mutations are present in the mesothelial lining, each prone to serve as a cell-of-origin of one of the distinct MPM subtypes illustrating that the cell-of-origin plays a pivotal role in determining the tumor subtype of MPM.[.]