Sex specific function of epithelial STAT3 signaling in pathogenesis of K-ras mutant lung cancer.
Sex specific function of epithelial STAT3 signaling in pathogenesis of K-ras mutant lung cancer.
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DOI：
10.1038/s41467-018-07042-y
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发表时间：
2018-11-02
影响因子：
16.6
通讯作者：
Moghaddam SJ
中科院分区：
文献类型：
--
作者：
Caetano MS;Hassane M;Van HT;Bugarin E;Cumpian AM;McDowell CL;Cavazos CG;Zhang H;Deng S;Diao L;Wang J;Evans SE;Behrens C;Wistuba II;Fuqua SAW;Lin H;Stabile LP;Watowich SS;Kadara H;Moghaddam SJ
K-ras癌基因突变的肺腺癌（LUAD）预后差。人们对驱动K-ras突变LUAD发生的促炎和免疫调节事件知之甚少。本研究建立了肺上皮特异性K-ras突变/Stat 3条件性基因敲除（LR/Stat 3 Δ/Δ）小鼠模型。上皮细胞Stat 3缺失导致有趣的性别相关差异;雌性LR/Stat 3 Δ/Δ小鼠中K-ras突变肿瘤减少，而雄性小鼠中肿瘤负荷增加。RNA测序和肿瘤微环境（TME）分析表明，女性Stat 3缺失后抗肿瘤免疫应答增加，相反，男性促肿瘤免疫途径升高。虽然雄性LR/Stat 3 Δ/Δ小鼠中的IL-6阻断降低了肺肿瘤发生，但雌性小鼠中雌激素受体信号传导的抑制增强了K-ras突变体肿瘤发生并将肺TME重编程为促肿瘤表型。我们的数据强调了K-ras突变LUAD中上皮Stat 3信号传导的关键性别特异性作用，从而为开发针对这种致命疾病的个性化（例如基于性别）免疫策略铺平了道路。促炎和免疫调节事件驱动K-ras突变型肺腺癌（LUAD）的发展知之甚少。在这里，他们开发了肺上皮特异性K-ras突变/Stat 3条件性敲除小鼠模型，并显示了上皮Stat 3信号在K-ras突变LUAD中的性别特异性作用。
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. 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.
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影响因子：
4
作者：
Egleston BL;Meireles SI;Flieder DB;Clapper ML
通讯作者：
Clapper ML
DOI：
10.1164/rccm.201309-1611oc
发表时间：
2014-04-01
影响因子：
24.7
作者：
Germain, Claire;Gnjatic, Sacha;Dieu-Nosjean, Marie-Caroline
通讯作者：
Dieu-Nosjean, Marie-Caroline
影响因子：
50.3
作者：
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通讯作者：
Coussens, Lisa M.
影响因子：
6.4
作者：
Ben Khedher, Soumaya;Neri, Monica;Stuker, Isabelle
通讯作者：
Stuker, Isabelle
影响因子：
168.9
作者：
Goldstraw, Peter;Ball, David;Shepherd, Frances A.
通讯作者：
Shepherd, Frances A.