Abstract 3974: Gender specific function of epithelial IL-6-STAT3 pathway in K-ras mutant lung cancer
Authors: Caetano Mauricio S. , Van Hieu , Bugarin Emmanuel , Cumpian Amber , McDowell Christina L. , Zhang Huiyuan , Evans Scott E. , Watowich Stephanie , Kadara Humam , Moghaddam Seyed J. 
Published: July 2017

Abstract
Activating mutations of K-ras are the most common oncogenic alterations found in lung cancer, and are heavily associated with tobacco exposure and poor prognosis. Using a conditional lung cancer mouse model (CC-LR), we showed that K-ras mutant lung tumors have inflammatory characteristics with activation of NF-kB pathway, release of IL-6 and activation of its downstream target, STAT3. We further demonstrated that IL-6 blockade results in significant tumor reduction as well as decreased pSTAT3 expression, tumor cell proliferation, angiogenesis and a reduction in tumor-associated immunosuppressive myeloid populations concomitant with induction of an anti-tumor phenotype. These indicate essential autocrine and paracrine roles for IL-6/STAT3 pathway in promotion of K-ras mutant lung cancer, largely via perpetuating inflammation introducing it as a vulnerability factor for this type of tumors. Here we generated a lung epithelial specific K-ras mutant/STAT3 conditional knockout mouse (LR/STAT3Δ/Δ) to further study the role of epithelial STAT3 activity in K-ras mutant lung cancer. We found that in female mice, lack of epithelial STAT3 inhibited lung cancer, and significantly decreased the lung inflammatory cell population, particularly macrophages, whereas in male mice, STAT3-deficiency surprisingly promoted lung cancer and significantly increased lung neutrophil population. To understand genome-wide mechanisms underlying this intriguing gender disparity, we performed RNA-sequencing of whole lungs from male and female LR/STAT3Δ/Δ and control CC-LR mice. Using a mixed effects model, we found 339 transcripts that were significantly modulated differently between LR/STAT3Δ/Δ and control CC-LR mice in males relative to females. Pathways and gene network analyses of the transcripts demonstrated that lungs of male LR/STAT3Δ/Δ mice exhibited markedly reduced Th1 immune T-cell signatures. We corroborated these findings and found significant phenotypic changes in the lung tumor microenvironment (TME) with males exhibiting increased pro-tumor inflammatory markers. Markedly, we found opposing IL-6 expression patterns with LR/STAT3Δ/Δ females expressing low IL-6 while LR/STAT3Δ/Δ males expressed high levels of IL-6. We then blocked IL-6 in male LR/STAT3Δ/Δ mice, which resulted in a significantly reduced lung tumorigenesis, and reformatted lung TME towards an anti-tumor phenotype with a Th1/CD8+ T cell signature. By contrast, estrogen receptor (ER) signaling blockade by tamoxifen in female LR/STAT3Δ/Δ mice promoted lung cancer, and reprogrammed lung TME toward a pro-tumor phenotype with an increase in Th17/Treg cell signature. Taken together, we conclude that epithelial STAT3 signaling has an important gender-specific role with autocrine and paracrine effects in K-ras induced lung tumorigenesis, which might be mediated by the interplay between ER signaling, and NF-κB mediated cytokine network.
Citation Format: Mauricio S. Caetano, Hieu Van, Emmanuel Bugarin, Amber Cumpian, Christina L. McDowell, Huiyuan Zhang, Scott E. Evans, Stephanie Watowich, Humam Kadara, Seyed J. Moghaddam. Gender specific function of epithelial IL-6-STAT3 pathway in K-ras mutant lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3974. doi:10.1158/1538-7445.AM2017-3974