Apoptosis has long been recognized as a significant mechanism for inhibiting tumor formation, and a plethora of stimuli can induce apoptosis during the progression and treatment of tumors. Moreover, tumor-derived apoptotic extracellular vesicles (apoEVs) are inevitably phagocytosed by live tumor cells, promoting tumor heterogeneity. Understanding the mechanism by which apoEVs regulate tumor cells is imperative for enhancing our knowledge of tumor metastasis and recurrence. Herein, we conducted a series of in vivo and in vitro experiments, and we report that tumor-derived apoEVs promoted lung adenocarcinoma (LUAD) metastasis, self-renewal and chemoresistance. Mechanistically, we demonstrated that apoEVs facilitated tumor metastasis and stemness by initiating the epithelial-mesenchymal transition program and upregulating the transcription of the stem cell factor SOX2. In addition, we found that ALDH1A1, which was transported by apoEVs, activated the NF-κB signaling pathway by increasing aldehyde dehydrogenase enzyme activity in recipient tumor cells. Furthermore, targeting apoEVs-ALDH1A1 significantly abrogated these effects. Collectively, our findings elucidate a novel mechanism of apoEV-dependent intercellular communication between apoptotic tumor cells and live tumor cells that promotes the formation of cancer stem cell-like populations, and these findings reveal that apoEVs-ALDH1A1 may be a potential therapeutic target and biomarker for LUAD metastasis and recurrence.

中文翻译：

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肿瘤源性凋亡细胞外囊泡介导的细胞间通讯促进肺腺癌的转移和干细胞性

细胞凋亡长期以来被认为是抑制肿瘤形成的重要机制，在肿瘤的进展和治疗过程中，大量的刺激可以诱导细胞凋亡。此外，肿瘤来源的凋亡细胞外囊泡（apoEV）不可避免地被活肿瘤细胞吞噬，促进肿瘤异质性。了解apoEVs调节肿瘤细胞的机制对于增强我们对肿瘤转移和复发的认识至关重要。在此，我们进行了一系列体内和体外实验，报告肿瘤来源的apoEVs促进肺腺癌（LUAD）转移、自我更新和化疗耐药。从机制上讲，我们证明apoEVs通过启动上皮-间质转化程序和上调干细胞因子SOX2的转录来促进肿瘤转移和干细胞性。此外，我们发现由apoEVs转运的ALDH1A1通过增加受体肿瘤细胞中乙醛脱氢酶的活性来激活NF-κB信号通路。此外，靶向 apoEVs-ALDH1A1 显着消除了这些效应。总的来说，我们的研究结果阐明了凋亡肿瘤细胞和活肿瘤细胞之间依赖 apoEV 的细胞间通讯的新机制，促进癌症干细胞样群的形成，这些发现表明 apoEVs-ALDH1A1 可能是潜在的治疗靶点和生物标志物用于LUAD转移和复发。