Understanding the impact of radiotherapy on the evolution of treatment resistant prostate cancer is critical for selecting effective treatment combinations. Whilst activation of Type 1 interferon signalling is a hallmark of how cells respond to viral infection, in cancer cells, multiple stresses are known to activate this same response. In this study we have evaluated for the first time the changes in the interferon response induced by culturing prostate cancer cells under sphere-forming conditions and following irradiation. We report a conserved upregulated transcript profile for both conditions that is strongly associated with therapeutic resistance and cell survival in vitro and in vivo. The profile includes and is regulated by the Type 1 interferon master regulator IRF7 which, when depleted, delays tumour re-growth following irradiation. We immuno-stained two independent prostate cohorts for IRF7 and found that increased expression, particularly in cases with low PTEN expression, correlated with poor prognosis. To more comprehensively characterise the impact of IRF7 and radiation on cells, RNA-Seq was performed on IRF7 knockdown cells at different radiation doses. We identified a number of biological processes that were IRF7-dependent, including the formation of stem-like cell populations and also therapeutic vulnerabilities. For example, irradiation sensitised surviving cells to either a combination of an IKKε/TBK1 and a MEK inhibitor or treatment with an inhibitor of IDO1, an IRF7-dependent gene. Translationally our work suggests that IRF7 expression can be used to stratify patients who may not benefit from receiving radiotherapy alone but rather may benefit from treatment combinations. In two cohorts treated with radical intent, strong IRF7 staining was associated with disease-specific death implicating this pathway as a convergence point for therapeutic resistance in prostate and potentially other cancer types.

中文翻译：

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IRF7 影响前列腺癌细胞响应辐射的存活

了解放射疗法对治疗耐药性前列腺癌演变的影响对于选择有效的治疗组合至关重要。虽然 1 型干扰素信号的激活是细胞如何应对病毒感染的标志，但在癌细胞中，已知多种压力会激活相同的反应。在这项研究中，我们首次评估了在球体形成条件下和照射后培养前列腺癌细胞诱导的干扰素反应的变化。我们报告了两种情况的保守上调转录谱，这两种情况与体外和体内的治疗耐药性和细胞存活密切相关。该配置文件包括 1 型干扰素主调节器 IRF7 并受其调节，IRF7 在耗尽时会延迟辐射后的肿瘤再生长。我们对两个独立的 IRF7 前列腺队列进行了免疫染色，发现表达增加，尤其是在 PTEN 表达较低的情况下，与不良预后相关。为了更全面地表征 IRF7 和辐射对细胞的影响，在不同辐射剂量下对 IRF7 敲低细胞进行了 RNA-Seq。我们确定了许多依赖 IRF7 的生物过程，包括干细胞样细胞群的形成以及治疗漏洞。例如，辐射使存活细胞对 IKKε/TBK1 和 MEK 抑制剂的组合或 IDO1 抑制剂（一种 IRF7 依赖性基因）的治疗敏感。从转化的角度来看，我们的工作表明 IRF7 表达可用于对可能无法从单独接受放疗中获益但可能从联合治疗中获益的患者进行分层。在接受激进治疗的两个队列中，强烈的 IRF7 染色与疾病特异性死亡有关，表明该通路是前列腺和其他潜在癌症类型治疗耐药性的汇聚点。