Author of

• 16549

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  P1.02 - Poster Session with Presenters Present (ID 454)

  • Event: WCLC 2016
  • Type: Poster Presenters Present
  • Track: Biology/Pathology
  • Presentations: 1
  • Moderators:
  • Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)

  • 16601

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    P1.02-052 - Signal Regulatory Protein a (SIRPA): A Key Regulator of the EGFR Pathway Demonstrates Both Tumor Suppressive and Oncogenic Properties (ID 6061)

    14:30 - 14:30  |  Author(s): W. Lam
    • Abstract

    Background:
    The epidermal growth factor receptor (EGFR) signaling pathway is one of the most frequently deregulated pathways in non-small cell lung cancer. While targeted therapy prolongs survival in patients harbouring EGFR mutations, resistance to treatment eventually develops in all cases. As multiple genetic and epigenetic alterations are known to disrupt signaling pathways, the objective of this study is to perform a multidimensional analysis of signaling pathways to identify alterations essential to tumorigenesis that are overlooked when assessing a single genomic dimension.
    
    Methods:
    Multidimensional integrative analysis of copy number, DNA methylation, and gene expression profiles of 77 lung adenocarcinomas and matched non-malignant tissues identified Signal Regulatory Protein A (SIRPA) as a novel candidate tumor suppressor gene. Following validation of genomic findings in multiple external data sets, the tumor suppressive effects of SIRPA were assessed in vitro and in vivo with a panel of lung cancer cell lines.
    
    Results:
    SIRPA negatively regulates receptor tyrosine kinase signaling through activation of the protein phosphatases SHP1 and SHP2 and was found to be underexpressed in 70% of lung tumours, ranking it in the 95[th] percentile of altered genes within the EGFR pathway. Immunohistochemistry (IHC) confirmed reduced protein expression in tumors, which was found to correlate with EGFR mutation and adenocarcinoma histology. In vitro, SIRPA knockdown promoted migration while simultaneously inducing a dramatic senescent phenotype, suggesting SIRPA may act as a barrier to tumorigenesis. This phenotype is dependent upon upregulation of the CDK inhibitor p27, which hypophosphorylates RB leading to cell cycle blockade and reduced tumor growth in vivo. Importantly, increased expression of p27 resulted in mis-localization into the cytoplasm where it is known to promote an invasive phenotype. Inhibition of p27 confirmed previous findings and emphasized the importance of this pathway in lung tumorigenesis. Surprisingly, overexpression of SIRPA increased cell growth and migration, suggesting SIRPA may also possess oncogenic properties due to its regulation of multiple signaling pathways. Overexpression of SHP2 following ectopic expression of SIRPA promotes migration through the inhibition of focal adhesions. This phenotype is abrogated upon siRNA knockdown of SHP2.
    
    Conclusion:
    SIRPA is an important player in lung tumor biology, capable of acting as both an oncogene and tumor suppressor due to its ability to regulate multiple signaling pathways. Due to the complex nature in its signaling, future work should focus on elucidating how the timing of alterations to SIRPA affects tumorigenesis to design treatment strategy.