Cancer stem cells (CSC) are highly resistant to conventional chemotherapeutic drugs. YAP1 and STAT3 are the two transcription factors that facilitate the therapeutic resistance and expansion of CSCs. The objective of this study was to understand the cross-talk between YAP1 and STAT3 activities and to determine the therapeutic efficacy of targeting dual CSC-regulating pathways (YAP1 and STAT3) combined with chemotherapy in lung adenocarcinoma. Here, we showed that YAP1 contributes to CSC regulation and enhances tumor formation while suppressing apoptosis. Mechanistically, YAP1 promotes phosphorylation of STAT3 by upregulating IL6. In lung adenocarcinoma clinical specimens, YAP1 expression correlated with that of IL6 (P < 0.01). More importantly, YAP1 and phosphorylated STAT3 (pSTAT3) protein expressions were significantly correlated (P < 0.0001) in primary lung adenocarcinoma as determined by IHC. Immunoblotting of 13 lung adenocarcinoma patient-derived xenografts (PDX) showed that all YAP1-expressing PDXs also exhibited pSTAT3. Additional investigations revealed that chemotherapy resistance and malignant stemness were influenced by upregulating NANOG, OCT4, and SOX2, and the expression of these targets significantly attenuated by genetically and pharmacologically hindering the activities of YAP1 and STAT3 in vivo and in vitro. Therapeutically, the dual inhibition of YAP1 and STAT3 elicits a long-lasting therapeutic response by limiting CSC expansion following chemotherapy in cell line xenograft and PDX models of lung adenocarcinoma. Collectively, these findings provide a conceptual framework to target the YAP1 and STAT3 pathways concurrently with systemic chemotherapy to improve the clinical management of lung adenocarcinoma, based on evidence that these two pathways expand CSC populations that mediate resistance to chemotherapy.

中文翻译：

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潜在癌症干细胞的同时靶向调节通路使肺腺癌对标准化疗敏感

癌症干细胞 (CSC) 对常规化疗药物具有高度抗性。YAP1 和 STAT3 是促进 CSC 治疗抵抗和扩增的两种转录因子。本研究的目的是了解 YAP1 和 STAT3 活性之间的相互影响，并确定靶向双 CSC 调节途径（YAP1 和 STAT3）联合化疗在肺腺癌中的治疗效果。在这里，我们发现 YAP1 有助于 CSC 调节并增强肿瘤形成，同时抑制细胞凋亡。从机制上讲，YAP1 通过上调 IL6 来促进 STAT3 的磷酸化。在肺腺癌临床标本中，YAP1 表达与 IL6 相关（P < 0.01）。更重要的是，YAP1 和磷酸化 STAT3 (pSTAT3) 蛋白表达显着相关（P < 0. 0001) 在 IHC 确定的原发性肺腺癌中。13 例肺腺癌患者来源的异种移植物 (PDX) 的免疫印迹表明，所有表达 YAP1 的 PDX 也表现出 pSTAT3。其他研究表明，化疗耐药和恶性干细胞受到上调 NANOG、OCT4 和 SOX2 的影响，并且这些靶标的表达通过在体内和体外的遗传和药理学上阻碍 YAP1 和 STAT3 的活性而显着减弱。在治疗上，YAP1 和 STAT3 的双重抑制通过在细胞系异种移植和肺腺癌 PDX 模型中限制化疗后的 CSC 扩增来引发持久的治疗反应。总的来说，