Division Signaling and Functional Genomics, German Cancer Research Center (DKFZ) and Heidelberg University, 69120, Heidelberg, Germany.
Department of Internal Medicine II of the Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany.
Nat Commun. 2019 May 16;10(1):2197. doi: 10.1038/s41467-019-09898-0.
In colorectal cancer (CRC), aberrant Wnt signalling is essential for tumorigenesis and maintenance of cancer stem cells. However, how other oncogenic pathways converge on Wnt signalling to modulate stem cell homeostasis in CRC currently remains poorly understood. Using large-scale compound screens in CRC, we identify MEK1/2 inhibitors as potent activators of Wnt/β-catenin signalling. Targeting MEK increases Wnt activity in different CRC cell lines and murine intestine in vivo. Truncating mutations of APC generated by CRISPR/Cas9 strongly synergize with MEK inhibitors in enhancing Wnt responses in isogenic CRC models. Mechanistically, we demonstrate that MEK inhibition induces a rapid downregulation of AXIN1. Using patient-derived CRC organoids, we show that MEK inhibition leads to increased Wnt activity, elevated LGR5 levels and enrichment of gene signatures associated with stemness and cancer relapse. Our study demonstrates that clinically used MEK inhibitors inadvertently induce stem cell plasticity, revealing an unknown side effect of RAS pathway inhibition.
在结直肠癌（CRC）中，异常的 Wnt 信号对于肿瘤发生和癌症干细胞的维持是必不可少的。然而，目前其他致癌途径如何汇集到 Wnt 信号以调节 CRC 中的干细胞动态平衡仍知之甚少。我们在 CRC 中使用大规模化合物筛选，发现 MEK1/2 抑制剂是 Wnt/β-catenin 信号的有效激活剂。靶向 MEK 会增加不同 CRC 细胞系和体内小鼠肠道中的 Wnt 活性。由 CRISPR/Cas9 生成的 APC 截断突变与 MEK 抑制剂强烈协同作用，增强同基因 CRC 模型中的 Wnt 反应。从机制上讲，我们证明 MEK 抑制会导致 AXIN1 的快速下调。使用源自患者的 CRC 类器官，我们表明 MEK 抑制会导致 Wnt 活性增加、LGR5 水平升高以及与干性和癌症复发相关的基因特征富集。我们的研究表明，临床上使用的 MEK 抑制剂会无意中诱导干细胞可塑性，揭示了 RAS 途径抑制的未知副作用。
