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Compensation between Wnt-driven tumorigenesis and cellular responses to ribosome biogenesis inhibition in the murine intestinal epithelium.
Cell Death and Differentiation ( IF 13.7 ) Pub Date : 2020-04-30 , DOI: 10.1038/s41418-020-0548-6
Aurélien Raveux 1, 2 , Aline Stedman 1, 3 , Sabrina Coqueran 1 , Sandrine Vandormael-Pournin 1 , Nick Owens 4 , Béatrice Romagnolo 5, 6, 7 , Michel Cohen-Tannoudji 1
Affiliation  

Ribosome biogenesis inhibition causes cell cycle arrest and apoptosis through the activation of tumor suppressor-dependent surveillance pathways. These responses are exacerbated in cancer cells, suggesting that targeting ribosome synthesis may be beneficial to patients. Here, we characterize the effect of the loss-of-function of Notchless (Nle), an essential actor of ribosome biogenesis, on the intestinal epithelium undergoing tumor initiation due to acute Apc loss-of-function. We show that ribosome biogenesis dysfunction strongly alleviates Wnt-driven tumor initiation by restoring cell cycle exit and differentiation in Apc-deficient progenitors. Conversely Wnt hyperactivation attenuates the cellular responses to surveillance pathways activation induced by ribosome biogenesis dysfunction, as proliferation was maintained at control-like levels in the stem cells and progenitors of double mutants. Thus, our data indicate that, while ribosome biogenesis inhibition efficiently reduces cancer cell proliferation in the intestinal epithelium, enhanced resistance of Apc-deficient stem and progenitor cells to ribosome biogenesis defects may be an important concern when using a therapeutic strategy targeting ribosome production for the treatment of Wnt-dependent tumorigenesis.

中文翻译:

Wnt 驱动的肿瘤发生与小鼠肠上皮细胞对核糖体生物发生抑制的反应之间的补偿。

核糖体生物发生抑制通过激活肿瘤抑制因子依赖性监测途径导致细胞周期停滞和细胞凋亡。这些反应在癌细胞中加剧,表明靶向核糖体合成可能对患者有益。在这里,我们描述了 Notchless (Nle) 功能丧失的影响,它是核糖体生物发生的重要参与者,对由于急性 Apc 功能丧失而发生肿瘤的肠上皮细胞的影响。我们表明,核糖体生物发生功能障碍通过恢复 Apc 缺陷祖细胞的细胞周期退出和分化来强烈缓解 Wnt 驱动的肿瘤起始。相反,Wnt 过度激活减弱了细胞对核糖体生物发生功能障碍诱导的监视途径激活的反应,因为在双突变体的干细胞和祖细胞中增殖维持在控制水平。因此,我们的数据表明,虽然核糖体生物发生抑制有效地减少了肠上皮细胞中的癌细胞增殖,但在使用靶向核糖体产生的治疗策略时,增强 Apc 缺陷型干细胞和祖细胞对核糖体生物发生缺陷的抵抗力可能是一个重要的问题。 Wnt依赖性肿瘤发生的治疗。
更新日期:2020-04-30
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