Background & aims

Aspirin reduces colorectal cancer (CRC) incidence and mortality. Understanding the biology responsible for this protective effect is key to developing biomarker-led approaches for rational clinical use. Wnt signalling drives CRC development from initiation to progression through regulation of epithelial-mesenchymal transition (EMT) and cancer stem cell populations (CSC). Here, we investigated whether aspirin can rescue these pro-invasive phenotypes associated with CRC progression in Wnt-driven human and mouse intestinal organoids.

Methods

We evaluated aspirin-mediated effects on phenotype and stem cell markers in intestinal organoids derived from mouse (Apc^Min/+ and Apc^flox/flox) and human familial adenomatous polyposis (FAP) patients. CRC cell lines (HCT116 and Colo205) were used to study effects on motility, invasion, Wnt signalling and EMT.

Results

Aspirin rescues the Wnt-driven cystic organoid phenotype by promoting budding in mouse and human Apc deficient organoids, which is paralleled by decreased stem cell marker expression. Aspirin-mediated Wnt inhibition in Apc^Min/+ mice is associated with EMT inhibition and decreased cell migration, invasion and motility in CRC cell lines. Chemical Wnt activation induces EMT and stem-like alterations in CRC cells, which are rescued by aspirin. Aspirin increases expression of the Wnt antagonist Dickkopf-1 (DKK-1) in CRC cells and organoids derived from FAP patients which contributes to EMT and CSC inhibition.

Conclusions

We provide evidence of phenotypic biomarkers of response to aspirin with an increased epithelial and reduced stem-like state mediated by an increase in DKK-1 This highlights a novel mechanism of aspirin-mediated Wnt inhibition and potential phenotypic and molecular biomarkers for trials.

中文翻译：

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阿司匹林可挽救人肠道类器官中 Wnt 驱动的干细胞样表型并增加 Wnt 拮抗剂 Dickkopf-1

背景与目标

阿司匹林可降低结直肠癌 (CRC) 的发病率和死亡率。了解负责这种保护作用的生物学是开发以生物标记为主导的合理临床使用方法的关键。Wnt 信号通过调节上皮-间质转化 (EMT) 和癌症干细胞群 (CSC) 驱动 CRC 从起始到进展的发展。在这里，我们研究了阿司匹林是否可以挽救这些与 Wnt 驱动的人类和小鼠肠道类器官中的 CRC 进展相关的促侵袭表型。

方法

我们评估了阿司匹林介导的对小鼠（Apc ^Min/+和 Apc ^flox/flox）和人类家族性腺瘤性息肉病 (FAP) 患者肠道类器官表型和干细胞标志物的影响。CRC 细胞系（HCT116 和 Colo205）用于研究对运动、侵袭、Wnt 信号和 EMT 的影响。

结果

阿司匹林通过促进小鼠和人类 Apc 缺陷类器官中的出芽来挽救 Wnt 驱动的囊性类器官表型，这与干细胞标记物表达降低相平行。^{Apc Min/+}小鼠中阿司匹林介导的 Wnt 抑制与 EMT 抑制和 CRC 细胞系中细胞迁移、侵袭和运动减少有关。化学 Wnt 激活诱导 CRC 细胞发生 EMT 和干细胞样改变，阿司匹林可挽救这些改变。阿司匹林增加 Wnt 拮抗剂 Dickkopf-1 (DKK-1) 在 FAP 患者的 CRC 细胞和类器官中的表达，这有助于抑制 EMT 和 CSC。

结论

我们提供了对阿司匹林反应的表型生物标志物的证据，DKK-1 增加介导的上皮细胞增加和干细胞样状态减少这突出了阿司匹林介导的 Wnt 抑制的新机制以及用于试验的潜在表型和分子生物标志物。