Tumor repopulation is a major cause of radiotherapy failure. Previous investigations highlighted that dying tumor cells played vital roles in tumor repopulation through promoting proliferation of the residual tumor repopulating cells (TRCs). However, TRCs also suffer DNA damage after radiotherapy, and might undergo mitotic catastrophe under the stimulation of proliferative factors released by dying cells. Hence, we intend to find out how these paradoxical biological processes coordinated to potentiate tumor repopulation after radiotherapy. Tumor repopulation models in vitro and in vivo were used for evaluating the therapy response and dissecting underlying mechanisms. RNA-seq was performed to find out the signaling changes and identify the significantly changed miRNAs. qPCR, western blot, IHC, FACS, colony formation assay, etc. were carried out to analyze the molecules and cells. Exosomes derived from dying tumor cells induced G1/S arrest and promoted DNA damage response to potentiate survival of TRCs through delivering miR-194-5p, which further modulated E2F3 expression. Moreover, exosomal miR-194-5p alleviated the harmful effects of oncogenic HMGA2 under radiotherapy. After a latent time, dying tumor cells further released a large amount of PGE2 to boost proliferation of the recovered TRCs, and orchestrated the repopulation cascades. Of note, low-dose aspirin was found to suppress pancreatic cancer repopulation upon radiation via inhibiting secretion of exosomes and PGE2. Exosomal miR-194-5p enhanced DNA damage response in TRCs to potentiate tumor repopulation. Combined use of aspirin and radiotherapy might benefit pancreatic cancer patients.

中文翻译：

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死于肿瘤细胞的外泌体miR-194-5p增强胰腺癌放疗后肿瘤繁殖细胞的存活和繁殖

肿瘤重新聚集是放疗失败的主要原因。先前的研究强调，垂死的肿瘤细胞通过促进残余肿瘤再生细胞（TRC）的增殖在肿瘤再生中起着至关重要的作用。但是，TRC在放疗后也会遭受DNA损伤，并且在垂死细胞释放的增殖因子的刺激下可能发生有丝分裂灾难。因此，我们打算发现这些矛盾的生物学过程如何协同作用以增强放疗后的肿瘤再形成。体外和体内肿瘤重现模型用于评估治疗反应和解剖潜在机制。进行RNA-seq以发现信号传导变化并鉴定显着变化的miRNA。qPCR，蛋白质印迹，IHC，FACS，集落形成分析等 进行了分析分子和细胞。来自垂死的肿瘤细胞的外泌体通过传递miR-194-5p来诱导G1 / S阻滞并促进DNA损伤反应，从而增强TRC的存活，从而进一步调节E2F3的表达。此外，外泌体miR-194-5p减轻了放射治疗下致癌性HMGA2的有害作用。一段潜在的时间后，垂死的肿瘤细胞进一步释放了大量的PGE2，以促进回收的TRC的增殖，并协调了重新分布的级联反应。值得注意的是，发现小剂量阿司匹林可通过抑制外泌体和PGE2的分泌来抑制辐射后胰腺癌的重新聚集。外泌体miR-194-5p增强了TRC中的DNA损伤反应，从而增强了肿瘤的再形成。阿司匹林和放疗的联合使用可能使胰腺癌患者受益。