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X. Han



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    ORAL 21 - Biology - Moving Beyond the Oncogene to Oncogene-Modifying Genes (ID 118)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      ORAL21.06 - Two Faces of YAP: Oncogenic in Lung Tumor Malignant Progression but Inhibitory in Phenotypic Transition (ID 2582)

      10:45 - 12:15  |  Author(s): X. Han

      • Abstract
      • Slides

      Background:
      Hippo signaling is actively involved in adult tissue homeostasis and cell fate determination. Previous studies have linked the activation of YAP (the major downstream effector of Hippo pathway) with LKB1 deficiency. Here, we characterize the function of YAP in the progression and phenotypic plasticity of LKB1-deficient lung tumors and decipher the detailed mechanisms underlying those process.

      Methods:
      Through integrative studies on human lung cancer specimens and lung cancer mouse models, we investigate the distinct role of YAP on lung cancer malignant progression and phenotypic transition. Furthermore, we uncover the detailed mechanisms by cell line based works together with biochemistry and molecular biology methods.

      Results:
      The oncogenic role of YAP in malignant progression of Lkb1-deficient lung adenocarcinoma Using distinct lung cancer mouse models, we show that ectopic expression of YAP in Type II alveolar epithelial cells results in hyperplasia in the lung. YAP expression significantly accelerates lung adenocarcinoma (ADC) malignant progression in Kras[G12D] mice whereas YAP deletion dramatically delays the process in Lkb1[L/L]/Kras[G12D] mice. Further mechanistic investigations have revealed that the delayed progression in Lkb1-deficient ADC with YAP ablation attribute to the downregulation of the inhibitor of apoptosis protein, Survivin. The inhibitory role of YAP in phenotypic transition from adenocarcinoma to squamous cell carcinoma We have previously shown LKB1 inactivation confers lung adenocarcinoma with strong plasticity to progressively change the cell fate and transit to squamous cell carcinoma with unknown mechanism. Here, we find that ectopic YAP overexpression dramatically inhibits ADC to SCC transdifferentiation whereas knockdown of YAP conversely accelerates the transition process. YAP is initially activated by LKB1 loss in ADC, leading to ZEB2 up-regulation in ADC cells, which binds to DNp63 gene promoter to repress DNp63 transcription. During the transition process, extracellular matrix (ECM) depletion in ADC inactivates YAP, thus relieves ZEB2 mediated default repression on DNp63 transcription in ADC, leading to the initiation of squamous differentiation program. Functionally, p63 ectopic expression significantly rescues the inhibitory effect of YAP upon SCC transdifferentiation.

      Conclusion:
      Our findings uncover the two faces of YAP in lung tumor malignant progression and phenotypic plasticity. YAP is an essential mediator of malignant progression of Lkb1-deficient lung ADC via regulating Survivin whereas an important barrier for lung cancer transdifferentiation through ZEB2 dependent DNp63 repression. Those works shed light on the fundamental role of YAP in regulating cancer progression and lineage phenotypic transition in LKB1 deficient lung tumors, which might help future development of better therapeutic strategies.

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