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D.N. Watkins

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    MINI 35 - Biology (ID 161)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI35.09 - Sonic Hedgehog Is Required for Tumor Progression in a Mouse Model of Small Cell Lung Cancer (ID 1103)

      18:30 - 20:00  |  Author(s): D.N. Watkins

      • Abstract
      • Slides

      Activation of the Hedgehog (Hh) signaling pathway is well documented in many cancers including Small Cell Lung Cancer (SCLC). Whilst it has been shown that Smoothened, the central Hh pathway mediator, is required for the initiation and progression of SCLC in a mouse model, it is unclear what drives activation of this pathway in these tumors. As these tumors commonly express the Sonic Hedgehog (Shh) ligand and lack pathway activating mutations, it was hypothesized that production of the Shh ligand by SCLC cells could be causing cell-autonomous pathway activation and thereby driving tumorigenesis.

      To address this question, we used a well-characterized conditional genetic mouse model of SCLC in which inhalation of recombinant adenovirus expressing Cre can trigger recombination at loxP sites in the airway epithelium. When the virus is administered to mice double homozygous for the conditional p53 and Rb knockout alleles (p53[lox/lox];Rb[lox/lox]), mice develop multiple tumors over 9 months. To define the role of the Shh ligand in the initiation and progression of SCLC in this tumor model, p53[lox/lox];Rb[lox/lox] animals were further crossed with a conditional Shh-overexpressing transgenic mouse (ShhTg). Reciprocally, genetic deletion of Shh was achieved by crossing p53[lox/lox];Rb[lox/lox ]mice with a conditional Shh knockout mouse (Shh[lox]).

      Aged cohorts of AdenoCre-infected p53[lox/lox];Rb[lox/lox];ShhTg mice developed more frequent and significantly larger tumors compared to their p53[lox/lox];Rb[lox/lox ]littermate controls, with tumors exhibiting a highly malignant and proliferative phenotype. Conversely, genetic deletion of Shh resulted in a dramatic reduction in tumor size in p53[lox/lox];Rb[lox/lox];Shh[lox/lox] mice compared to littermate controls.

      Together, these findings demonstrate that Shh plays a crucial role in driving the progression of SCLC, suggesting that Shh may be a potentially useful therapeutic target.

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