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BCL9/9L-@b-catenin Signaling is Associated With Poor Outcome in Colorectal Cancer

机译：BCL9 / 9L- @ b-catenin信号传导与大肠癌预后不良相关

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BCL9/9L proteins enhance the transcriptional output of the @b-catenin/TCF transcriptional complex and contribute critically to upholding the high WNT signaling level required for stemness maintenance in the intestinal epithelium. Here we show that a BCL9/9L-dependent gene signature derived from independent mouse colorectal cancer (CRC) models unprecedentedly separates patient subgroups with regard to progression free and overall survival. We found that this effect was by and large attributable to stemness related gene sets. Remarkably, this signature proved associated with recently described poor prognosis CRC subtypes exhibiting high stemness and/or epithelial-to-mesenchymal transition (EMT) traits. Consistent with the notion that high WNT signaling is required for stemness maintenance, ablating Bcl9/9l-@b-catenin in murine oncogenic intestinal organoids provoked their differentiation and completely abrogated their tumorigenicity, while not affecting their proliferation. Therapeutic strategies aimed at targeting WNT responses may be limited by intestinal toxicity. Our findings suggest that attenuating WNT signaling to an extent that affects stemness maintenance without disturbing intestinal renewal might be well tolerated and prove sufficient to reduce CRC recurrence and dramatically improve disease outcome.
机译：BCL9 / 9L蛋白可增强@ b-catenin / TCF转录复合物的转录输出，并在维持肠道上皮干性维持所需的高WNT信号水平方面起关键作用。在这里，我们显示了源自独立小鼠结肠直肠癌（CRC）模型的BCL9 / 9L依赖性基因签名在无进展生存期和总体生存率方面前所未有地分离了患者亚组。我们发现，这种影响在很大程度上归因于与干性相关的基因集。值得注意的是，该特征证明与最近描述的预后较差的CRC亚型有关，这些亚型表现出高干性和/或上皮-间质转化（EMT）特征。与维持茎干需要高WNT信号传递的观点相一致，在鼠类致癌性肠类器官中消融Bcl9 / 9l @ b-catenin会激发它们的分化并完全消除其致瘤性，同时不影响其增殖。旨在针对WNT反应的治疗策略可能会受到肠毒性的限制。我们的发现表明，在不干扰肠道更新的情况下将WNT信号减弱至影响茎维持的程度可能是良好的耐受性，并证明足以减少CRC复发并显着改善疾病预后。

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