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Francesc López-Giráldez

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    MA17 - Molecular Mechanisms and Therapies (ID 143)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Biology
    • Presentations: 1
    • Now Available
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      MA17.01 - Cell Lineage and Chromatin Landscape of Lung Cancer Are Controlled by GATA6 (Now Available) (ID 59)

      15:45 - 17:15  |  Author(s): Francesc López-Giráldez

      • Abstract
      • Presentation
      • Slides


      Thoracic malignancies are histologically and biologically heterogeneous. The underlying causes of this heterogeneity are believed to be linked to the complex cellular ontogenies of lung cancers and their relationship to pulmonary development. Lineage selective transcription factors (TFs) are critical determinants of airway cell differentiation and homeostasis, but their biological requirements are often conditional. Analogously, several developmental TFs can paradoxically enhance or inhibit lung cancer progression, depending on cellular and epigenetic contexts which remain largely undefined. In this study, we report a novel function for the endodermal and pulmonary specifying TF GATA6 in lung cancer.


      To understand the role of GATA6 in lung tumorigenesis we used a genetically engineer mouse model (GEMMs) harboring Kras p53 mutations using progenitor cell specific gene targeting. We combined GEMMs biology with integrated analysis of the transcriptome and the chromatin landscape of lung cells derived from GATA6 deficient tumors.


      In this study, we uncover a conditional role for the endodermal and pulmonary specifying TF GATA6 during the initiation and progression of Kras mutant lung adenocarcinoma (LUAD). Inhibition of Gata6 in genetically engineered mouse models dampens the proliferation and increases the differentiation of LUAD tumors. These effects are influenced by the epithelial cell type that is targeted for transformation, demonstrating that GATA6 expression is an important molecular determinant of the cell of origin in Kras mutant lung cancer. In LUAD cells derived from surfactant protein C expressing progenitors, we identify multiple genomic loci that are bound by GATA6. Moreover, suppression of Gata6 in these cells significantly alters chromatin accessibility, particularly at distal enhancer elements. Analogous to its paradoxical activity in the developing lungs, GATA6 expression fluctuates during different stages of LUAD progression and can epigenetically control diverse lineage programs associated with cell proliferation, alveolar specification, BMP signaling, and epithelial plasticity.

      In summary:

      1) GATA6 expression varies during different stages of disease progression in the lung adenocarcinoma (LUAD) subtype

      2) Suppression of Gata6 can diminish the proliferation and progression of LUAD in a manner that is influenced by the transforming progenitor of origin

      3) GATA6 differentially modulates chromatin accessibility across the genome of LUAD cells

      4) This epigenomic mechanism results in the activation of different lineage specific programs, including the BMP signaling pathway.


      These findings reveal how GATA6 can modulate the chromatin landscape of lung cancer cells to control their divergent lineage dependencies during tumor progression.

      D.X.N. has received research funding from AstraZeneca, Inc.

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