Aspirin-mediated DKK-1 increase rescues Wnt-driven stem-like phenotype in human intestinal organoids
Aspirin-mediated DKK-1 increase rescues Wnt-driven stem-like phenotype in human intestinal organoids
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DOI：
10.1101/809517
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发表时间：
2019-10
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通讯作者：
Karen J Dunbar;A. Valanciuté;V. Rajasekaran;T. Jamieson;Paz Freile Vinuela;Ana Lima;J. Blackmur;Anna-Maria Ochocka-Fox;M. Arends;O. Sansom;K. Myant;S. Farrington;M. Dunlop;F. Din
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作者：
Karen J Dunbar;A. Valanciuté;V. Rajasekaran;T. Jamieson;Paz Freile Vinuela;Ana Lima;J. Blackmur;Anna-Maria Ochocka-Fox;M. Arends;O. Sansom;K. Myant;S. Farrington;M. Dunlop;F. Din
阿司匹林可降低结直肠癌的发病率和死亡率。WNT信号通过调节上皮-间充质转化(EMT)和肿瘤干细胞群(CSC)，推动结直肠癌从起始到进展。在这里，我们研究了阿司匹林是否可以挽救Wnt驱动的人类和小鼠肠道器官中与CRC进展相关的这些前侵袭性表型。阿司匹林通过促进小鼠和人类APC缺陷的囊状器官的萌发来挽救Wnt驱动的囊状器官表型，这与干细胞标记物表达减少是平行的。在ApcMin/+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、侵袭和运动能力的降低有关。化学Wnt激活诱导结直肠癌细胞发生EMT和干细胞样改变，而阿司匹林可以挽救这种改变。阿司匹林增加Wnt拮抗剂Dickkopf-1(DKK-1)在结直肠癌细胞和FAP患者来源的器官中的表达。我们提供了阿司匹林的表型生物标记物的证据，通过DKK-1的增加介导了上皮细胞的增加和干细胞样状态的减少。因此，我们强调了阿司匹林介导的Wnt抑制的新机制，以及潜在的表型和分子生物标记物。
Aspirin reduces the incidence and mortality of colorectal cancer (CRC). 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. 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 ApcMin/+ 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. We provide evidence of phenotypic biomarkers of aspirin response with an increased epithelial and reduced stem-like state mediated by an increase in DKK-1. Thus we highlight a novel mechanism of aspirin-mediated Wnt inhibition and potential phenotypic and molecular biomarkers for trials.