Aspirin Rescues Wnt-Driven Stem-like Phenotype in Human Intestinal Organoids and Increases the Wnt Antagonist Dickkopf-1.
Aspirin Rescues Wnt-Driven Stem-like Phenotype in Human Intestinal Organoids and Increases the Wnt Antagonist Dickkopf-1.
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DOI：
10.1016/j.jcmgh.2020.09.010
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发表时间：
2021
影响因子：
7.2
通讯作者：
Din FVN
中科院分区：
文献类型：
--
作者：
Dunbar K;Valanciute A;Lima ACS;Vinuela PF;Jamieson T;Rajasekaran V;Blackmur J;Ochocka-Fox AM;Guazzelli A;Cammareri P;Arends MJ;Sansom OJ;Myant KB;Farrington SM;Dunlop MG;Din FVN
阿司匹林可降低结直肠癌(CRC)的发病率和死亡率。了解对这种保护作用负责的生物学是开发生物标记物引导的合理临床使用方法的关键。WNT信号通过调节上皮-间充质转化(EMT)和肿瘤干细胞群，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进展相关的这些侵袭前表型。我们评估了阿司匹林对来自小鼠(ApcMin/+和Apcflx/FLOX)和人类家族性腺瘤性息肉病患者的肠道器官的表型和干细胞标志物的影响。以结直肠癌细胞系(HCT116和Colo205)为研究对象，研究其对细胞运动、侵袭、Wnt信号和EMT的影响。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在结直肠癌细胞和家族性腺瘤性息肉病患者的器官中的表达，这有助于EMT和癌症干细胞抑制。我们提供了阿司匹林反应的表型生物标志物的证据，通过增加Dickkopf-1来调节上皮细胞的增加和干细胞状态的减少。这突出了阿司匹林介导的Wnt抑制的新机制和潜在的表型和分子生物标记物用于试验。
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 signaling drives CRC development from initiation to progression through regulation of epithelial-mesenchymal transition (EMT) and cancer stem cell populations. Here, we investigated whether aspirin can rescue these proinvasive phenotypes associated with CRC progression in Wnt-driven human and mouse intestinal organoids. We evaluated aspirin-mediated effects on phenotype and stem cell markers in intestinal organoids derived from mouse (ApcMin/+ and Apcflox/flox) and human familial adenomatous polyposis patients. CRC cell lines (HCT116 and Colo205) were used to study effects on motility, invasion, Wnt signaling, and EMT. 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 in CRC cells and organoids derived from familial adenomatous polyposis patients, which contributes to EMT and cancer stem cell inhibition. We provide evidence of phenotypic biomarkers of response to aspirin with an increased epithelial and reduced stem-like state mediated by an increase in Dickkopf-1. This highlights a novel mechanism of aspirin-mediated Wnt inhibition and potential phenotypic and molecular biomarkers for trials.
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影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
通讯作者：
Hamilton PW
影响因子：
29.4
作者：
Farin, Henner F.;Van Es, Johan H.;Clevers, Hans
通讯作者：
Clevers, Hans
DOI：
10.15252/embj.201591739
发表时间：
2015-09-14
期刊：
The EMBO journal
影响因子：
--
作者：
Huels DJ;Ridgway RA;Radulescu S;Leushacke M;Campbell AD;Biswas S;Leedham S;Serra S;Chetty R;Moreaux G;Parry L;Matthews J;Song F;Hedley A;Kalna G;Ceteci F;Reed KR;Meniel VS;Maguire A;Doyle B;Söderberg O;Barker N;Watson A;Larue L;Clarke AR;Sansom OJ
通讯作者：
Sansom OJ
影响因子：
2.7
作者：
Brabletz, T;Hlubek, F;Kirchner, T
通讯作者：
Kirchner, T
影响因子：
8
作者：
Gonzálex-Sancho, JM;Aguilera, O;Muñoz, A
通讯作者：
Muñoz, A