Journal Article

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

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

2018

Overview

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/ Stat3 Δ/Δ ) mouse model. Epithelial Stat3 deletion results in intriguing sex-associated discrepancies; K-ras mutant tumors are decreased in female LR/ Stat3 Δ/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/ Stat3 Δ/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. Proinflammatory and immunomodulatory events that drive development of K-ras mutant lung adenocarcinoma (LUAD) are poorly understood. Here they develop a lung epithelial specific K-ras mutant/ Stat3 conditional knockout mouse model and show a sex-specific role for epithelial Stat3 signaling in K-ras -mutant LUAD.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38 / 38/1 / 38/77 / 38/91 / 45 / 59 / 631/250 / 631/67 / 631/67/1612 / 631/67/580 / 64 / 64/60 / 82/1 / 82/51 / 96 / 96/21 / 96/95 / Estrogens / Females / Gene sequencing / Humanities and Social Sciences / Immune response / Immunomodulation / Inflammation / Interleukin 6 / K-Ras protein / Lung cancer / Males / multidisciplinary / Mutants / Mutation / Pathogenesis / Phenotypes / Ribonucleic acid / RNA / Science / Science (multidisciplinary) / Sex / Signaling / Stat3 protein / Tumorigenesis / Tumors