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

Mauricio S. Caetano, Maya Hassane, Hieu T. Van, Emmanuel Bugarin, Amber M. Cumpian, Christina L. McDowell, Carolina Gonzalez Cavazos, Huiyuan Zhang, Shanshan Deng, Lixia Diao, Jing Wang, Scott E. Evans, Carmen Behrens, Ignacio I. Wistuba, Susan A. W. Fuqua, Huang Lin, Laura P. Stabile, Stephanie S. Watowich, Humam Kadara () and Seyed Javad Moghaddam ()
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Mauricio S. Caetano: The University of Texas MD Anderson Cancer Center
Maya Hassane: American University of Beirut
Hieu T. Van: The University of Texas MD Anderson Cancer Center
Emmanuel Bugarin: The University of Texas MD Anderson Cancer Center
Amber M. Cumpian: The University of Texas MD Anderson Cancer Center
Christina L. McDowell: The University of Texas MD Anderson Cancer Center
Carolina Gonzalez Cavazos: The University of Texas MD Anderson Cancer Center
Huiyuan Zhang: The University of Texas MD Anderson Cancer Center
Shanshan Deng: The University of Texas MD Anderson Cancer Center
Lixia Diao: The University of Texas MD Anderson Cancer Center
Jing Wang: The University of Texas MD Anderson Cancer Center
Scott E. Evans: The University of Texas MD Anderson Cancer Center
Carmen Behrens: The University of Texas MD Anderson Cancer Center
Ignacio I. Wistuba: The University of Texas MD Anderson Cancer Center
Susan A. W. Fuqua: Baylor College of Medicine
Huang Lin: University of Pittsburgh
Laura P. Stabile: University of Pittsburgh
Stephanie S. Watowich: The University of Texas MD Anderson Cancer Center
Humam Kadara: American University of Beirut
Seyed Javad Moghaddam: The University of Texas MD Anderson Cancer Center

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: Abstract Lung adenocarcinomas (LUADs) with mutations in the K-ras oncogene display dismal prognosis. Proinflammatory and immunomodulatory events that drive development of K-ras mutant LUAD are poorly understood. Here, we develop a lung epithelial specific K-ras mutant/Stat3 conditional knockout (LR/Stat3Δ/Δ) mouse model. Epithelial Stat3 deletion results in intriguing sex-associated discrepancies; K-ras mutant tumors are decreased in female LR/Stat3Δ/Δ mice whereas tumor burdens are increased in males. RNA-sequencing and tumor microenvironment (TME) analysis demonstrate increased anti-tumor immune responses following Stat3 deletion in females and, conversely, elevated pro-tumor immune pathways in males. While IL-6 blockade in male LR/Stat3Δ/Δ mice reduces lung tumorigenesis, inhibition of estrogen receptor signaling in female mice augments K-ras mutant oncogenesis and reprograms lung TME toward a pro-tumor phenotype. Our data underscore a critical sex-specific role for epithelial Stat3 signaling in K-ras mutant LUAD, thus paving the way for developing personalized (e.g. sex-based) immunotherapeutic strategies for this fatal disease.

Date: 2018
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DOI: 10.1038/s41467-018-07042-y

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