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Caetano, Mauricio S.; Hassane, Maya; Van, Hieu T.; Bugarin, Emmanuel; Cumpian, Amber M.; McDowell, Christina L.; Cavazos, Carolina Gonzalez; Zhang, Huiyuan; Deng, Shanshan; Diao, Lixia; Wang, Jing; Evans, Scott E.; Behrens, Carmen; Wistuba, Ignacio I.; Fuqua, Susan A. W.; Lin, Huang; Stabile, Laura P.; Watowich, Stephanie S.; Kadara, Humam; Moghaddam, Seyed Javad

Sex specific function of epithelial STAT3 signaling in pathogenesis of K-ras mutant lung cancer

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  • Media type: E-Article
  • Title: Sex specific function of epithelial STAT3 signaling in pathogenesis of K-ras mutant lung cancer
  • Contributor: Caetano, Mauricio S.; Hassane, Maya; Van, Hieu T.; Bugarin, Emmanuel; Cumpian, Amber M.; McDowell, Christina L.; Cavazos, Carolina Gonzalez; Zhang, Huiyuan; Deng, Shanshan; Diao, Lixia; Wang, Jing; Evans, Scott E.; Behrens, Carmen; Wistuba, Ignacio I.; Fuqua, Susan A. W.; Lin, Huang; Stabile, Laura P.; Watowich, Stephanie S.; Kadara, Humam; Moghaddam, Seyed Javad
  • Published: Springer Science and Business Media LLC, 2018
  • Published in: Nature Communications, 9 (2018) 1
  • Language: English
  • DOI: 10.1038/s41467-018-07042-y
  • ISSN: 2041-1723
  • Keywords: General Physics and Astronomy ; General Biochemistry, Genetics and Molecular Biology ; General Chemistry ; Multidisciplinary
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title><jats:p>Lung adenocarcinomas (LUADs) with mutations in the <jats:italic>K-ras</jats:italic> oncogene display dismal prognosis. Proinflammatory and immunomodulatory events that drive development of <jats:italic>K-ras</jats:italic> mutant LUAD are poorly understood. Here, we develop a lung epithelial specific <jats:italic>K-ras</jats:italic> mutant/<jats:italic>Stat3</jats:italic> conditional knockout (LR/<jats:italic>Stat3</jats:italic><jats:sup>Δ/Δ</jats:sup>) mouse model. Epithelial <jats:italic>Stat3</jats:italic> deletion results in intriguing sex-associated discrepancies; <jats:italic>K-ras</jats:italic> mutant tumors are decreased in female LR/<jats:italic>Stat3</jats:italic><jats:sup>Δ/Δ</jats:sup> mice whereas tumor burdens are increased in males. RNA-sequencing and tumor microenvironment (TME) analysis demonstrate increased anti-tumor immune responses following <jats:italic>Stat3</jats:italic> deletion in females and, conversely, elevated pro-tumor immune pathways in males. While IL-6 blockade in male LR/<jats:italic>Stat3</jats:italic><jats:sup>Δ/Δ</jats:sup> mice reduces lung tumorigenesis, inhibition of estrogen receptor signaling in female mice augments <jats:italic>K-ras</jats:italic> mutant oncogenesis and reprograms lung TME toward a pro-tumor phenotype. Our data underscore a critical sex-specific role for epithelial <jats:italic>Stat3</jats:italic> signaling in <jats:italic>K-ras</jats:italic> mutant LUAD, thus paving the way for developing personalized (e.g. sex-based) immunotherapeutic strategies for this fatal disease.</jats:p>
  • Access State: Open Access