Abstract：
Metastatic lung adenocarcinoma (LuAC) presents a significant clinical challenge due to the short latency and the lack of efficient treatment options. Therefore, identification of molecular vulnerabilities in metastatic LuAC holds great importance in the development of therapeutic drugs against this disease. In this study, we performed a genome-wide siRNA screening using poorly and highly brain-metastatic LuAC cell lines. Using this approach, we discovered that compared to poorly metastatic LuAC (LuAC-Par) cells, brain-metastatic LuAC (LuAC-BrM) cells exhibited a significantly higher vulnerability to c-FLIP (an inhibitor of caspase-8)-depletion-induced apoptosis. Furthermore, in vivo studies demonstrated that c-FLIP knockdown specifically inhibited growth of LuAC-BrM, but not the LuAC-Par, tumors, suggesting the addiction of LuAC-BrM to the function of c-FLIP for their survival. Our in vitro and in vivo analyses also demonstrated that LuAC-BrM is more sensitive to c-FLIP-depletion due to ER stress-induced activation of the c-JUN and subsequent induction of stress genes including ATF4 and DDIT3. Finally, we found that c-JUN not only sensitized LuAC-BrM to c-FLIP-depletion-induced cell death but also promoted brain metastasis in vivo, providing strong evidence for c-JUN\'s function as a double-edged sword in LuAC-BrM. Collectively, our findings not only reveal a novel link between c-JUN, brain metastasis, and c-FLIP addiction in LuAC-BrM but also present an opportunity for potential therapeutic intervention.
摘要：
转移性肺腺癌（LuAC）由于潜伏期短和缺乏有效的治疗选择而提出了重大的临床挑战。因此,识别转移性LuAC中的分子脆弱性对于开发针对该疾病的治疗药物非常重要。在这项研究中,我们使用低脑转移和高度脑转移的LuAC细胞系进行了全基因组siRNA筛选.使用这种方法，我们发现，与低转移性LuAC（LuAC-Par）细胞相比，脑转移LuAC（LuAC-BrM）细胞对c-FLIP（caspase-8的抑制剂）耗竭诱导的凋亡表现出更高的脆弱性。此外，体内研究表明，c-FLIP敲除特异性抑制LuAC-BrM的生长，但不是LuAC-Par,肿瘤，表明LuAC-BrM对c-FLIP的存活功能成瘾。我们的体外和体内分析还表明，由于ER应激诱导的c-JUN激活以及随后诱导的包括ATF4和DDIT3的应激基因，LuAC-BrM对c-FLIP消耗更敏感。最后,我们发现c-JUN不仅使LuAC-BrM对c-FLIP耗竭诱导的细胞死亡敏感，而且在体内促进脑转移，为c-JUN在LuAC-BrM中作为一把双刃剑的功能提供了有力的证据。总的来说，我们的发现不仅揭示了C-JUN之间的一种新颖的联系，脑转移瘤,LuAC-BrM中的c-FLIP成瘾，但也为潜在的治疗干预提供了机会。
