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X. Han

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    ORAL 07 - Lung Cancer Pathogenesis (ID 91)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      ORAL07.07 - Evidence and Mechanism for the Transdifferentiation of Lung Adenocarcinoma to Squamous Cell Carcinoma (ID 2550)

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

      • Abstract
      • Slides

      Non-small-cell lung cancer (NSCLC) is featured with genetic and histopathological heterogeneity. LKB1-mutant NSCLC represents a unique and prevalent molecular subtype with limited treatment options. Originally characterized as a tumor suppressor, LKB1 phosphorylates and activates several downstream targets to inhibit cell growth; on the other hand, LKB1 also regulates cellular energy sensing and metabolic homeostasis. This raises an interesting question about how LKB1 inactivation coordinates in vivo lung tumor progression with metabolic adaptation. We have shown recently that the Kras/Lkb1 lung tumor heterogeneity results from p63-mediated ADC to SCC transdifferentiation (AST) through mixed Ad-SCC at late stage, suggesting an unexpected plasticity upon LKB1 inactivation in NSCLC. However, it remains unclear how LKB1 inactivation coordinates tumor progression with metabolic adaptation in orchestrating this tumor plasticity.

      We integratively analyze the transdifferention process of mouse lung adenocarcinoma to squamous cell carcinoma in Kras/Lkb1 Adeno-Cre nasal inhalation model as well as the lineage-defined Kras/Lkb1 model. Moreover, we have also systematically analyzed the clinical lung adenosquamous cell carcinoma to prove the findings from our animal models.

      Here in Kras[G12D];Lkb1[lox/lox ](KL) mouse model, we reveal differential reactive oxygen species (ROS) levels in lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC). ROS can functionally modulate the ADC-to-SCC transdifferentiation (AST). Furthermore, pentose phosphate pathway deregulation and impaired fatty acid oxidation collectively contribute to the redox imbalance and functionally affect AST. Similar tumor and redox heterogeneity also exist in human NSCLC with LKB1 inactivation. In preclinical trials towards metabolic stress, certain KL ADC can develop drug resistance through squamous transdifferentiation. This study uncovers critical redox control of tumor plasticity that may affect therapeutic response in NSCLC.

      LKB1-mutant tumor represents a unique and prevalent molecular subtype of NSCLC with limited treatment options. Through integrative human lung cancer sample analysis and modeling tumor development in mouse model, we have uncovered the accumulation of ROS during ADC progression, which modulates the phenotypic transition as squamous transdifferentiation and metabolic adaptation. This metabolic adaptation reflects the dynamic function of LKB1: a tumor suppressor at early lung ADC progression and an essential metabolic regulator at late phenotypic transition. The redox-controlled tumor plasticity for squamous transdifferentiation enables ADC to progress under stress, and more importantly to escape certain treatment towards cancer metabolism. The plasticity represents as a potentially important mechanism for lung cancer metabolic adaptation and drug resistance, and holds important therapeutic implications.

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