Radiation therapy, one of the most effective therapies to treat cancer, is highly toxic to healthy tissue. The delivery of radiation at ultra-high dose rates, FLASH radiation therapy (FLASH), has been shown to maintain therapeutic anti-tumor efficacy while sparing normal tissues compared to conventional dose rate irradiation (CONV). Though promising, these studies have been limited mainly to murine models. Here, we leveraged enteroids, three-dimensional cell clusters that mimic the intestine, to study human-specific tissue response to radiation. We observed enteroids have a greater colony growth potential following FLASH compared with CONV. In addition, the enteroids that reformed following FLASH more frequently exhibited proper intestinal polarity. While we did not observe differences in enteroid damage across groups, we did see distinct transcriptomic changes. Specifically, the FLASH enteroids upregulated the expression of genes associated with the WNT-family, cell-cell adhesion, and hypoxia response. These studies validate human enteroids as a model to investigate FLASH and provide further evidence supporting clinical study of this therapy. Insight Box Promising work has been done to demonstrate the potential of ultra-high dose rate radiation (FLASH) to ablate cancerous tissue, while preserving healthy tissue. While encouraging, these findings have been primarily observed using pre-clinical murine and traditional two-dimensional cell culture. This study validates the use of human enteroids as a tool to investigate human-specific tissue response to FLASH. Specifically, the work described demonstrates the ability of enteroids to recapitulate previous in vivo findings, while also providing a lens through which to probe cellular and molecular-level responses to FLASH. The human enteroids described herein offer a powerful model that can be used to probe the underlying mechanisms of FLASH in future studies.

中文翻译：

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人类肠类作为研究常规和超高剂量率辐射的工具。

放射治疗是治疗癌症最有效的疗法之一，但对健康组织具有剧毒。与传统剂量率照射 (CONV) 相比，超高剂量率放射治疗 (FLASH) 已被证明可以保持抗肿瘤疗效，同时不伤害正常组织。尽管前景广阔，但这些研究主要局限于小鼠模型。在这里，我们利用肠类（模仿肠道的三维细胞簇）来研究人类特定组织对辐射的反应。我们观察到，与 CONV 相比，FLASH 后肠类具有更大的集落生长潜力。此外，FLASH后重组的肠样更频繁地表现出适当的肠极性。虽然我们没有观察到各组肠样损伤的差异，但我们确实看到了明显的转录组变化。具体来说，FLASH 小肠上调了与 WNT 家族、细胞间粘附和缺氧反应相关的基因的表达。这些研究验证了人类肠类作为研究 FLASH 的模型，并为支持该疗法的临床研究提供了进一步的证据。Insight Box 已经开展了一些有前途的工作，证明超高剂量率辐射 (FLASH) 消融癌组织同时保留健康组织的潜力。虽然令人鼓舞，但这些发现主要是通过临床前小鼠和传统的二维细胞培养观察到的。这项研究验证了使用人类肠类作为研究人类特定组织对 FLASH 反应的工具。具体来说，所描述的工作展示了肠类化合物重现先前体内发现的能力，同时还提供了一个镜头来探测细胞和分子水平对 FLASH 的反应。本文描述的人类肠类提供了一个强大的模型，可用于在未来的研究中探讨 FLASH 的潜在机制。