Sex specific function of epithelial STAT3 signaling in pathogenesis of K-ras mutant lung cancer
Year: 2018
Type: article
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.
Source: Nature Communications
Authors: 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, Seyed Javad Moghaddam
Institutions: The University of Texas MD Anderson Cancer Center, American University of Beirut, Tecnológico de Monterrey, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Baylor College of Medicine, University of Pittsburgh, UPMC Hillman Cancer Center, University of Pittsburgh Medical Center, The University of Texas Health Science Center at Houston
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
Awards: G3597013422, G4727816275, G4985569203
OpenAlex ID: W2899055178