Cell type-dependent differential activation of ERK by oncogenic KRAS in colon cancer and intestinal epithelium
Cell type-dependent differential activation of ERK by oncogenic KRAS in colon cancer and intestinal epithelium
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DOI：
10.1038/s41467-019-10954-y
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发表时间：
2019-07-02
影响因子：
16.6
通讯作者：
Morkel, Markus
中科院分区：
文献类型：
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作者：
Brandt, Raphael;Sell, Thomas;Morkel, Markus
KRAS或BRAF的致癌突变在结直肠癌中常见，并激活ERK激酶。在这里，我们发现分级ERK磷酸化与有和没有KRAS突变的患者来源的结直肠癌类器官中的细胞分化相关。使用报告基因、单细胞转录组学和质谱细胞术，我们观察到小鼠肠类器官中响应转基因KRAS（G12 V）的ERK的细胞类型特异性磷酸化，而转基因BRAF（V600 E）在所有细胞中激活ERK。从扰动数据的定量网络建模显示，ERK的激活是由细胞类型特异性MEK到ERK前馈和负反馈信号传导形成的。我们确定双特异性磷酸酶作为候选人的ERK在肠道中的调制器。此外，我们发现致癌KRAS与β-连环蛋白一起有利于具有高ERK活性的隐窝细胞的扩增。我们的实验突出了结直肠癌中致癌BRAF和KRAS之间的关键差异，并发现了与癌症治疗基本相关的信号通路中的意外异质性。
Oncogenic mutations in KRAS or BRAF are frequent in colorectal cancer and activate the ERK kinase. Here, we find graded ERK phosphorylation correlating with cell differentiation in patient-derived colorectal cancer organoids with and without KRAS mutations. Using reporters, single cell transcriptomics and mass cytometry, we observe cell type-specific phosphorylation of ERK in response to transgenic KRAS(G12V) in mouse intestinal organoids, while transgenic BRAF(V600E) activates ERK in all cells. Quantitative network modelling from perturbation data reveals that activation of ERK is shaped by cell type-specific MEK to ERK feed forward and negative feedback signalling. We identify dual-specificity phosphatases as candidate modulators of ERK in the intestine. Furthermore, we find that oncogenic KRAS, together with beta-Catenin, favours expansion of crypt cells with high ERK activity. Our experiments highlight key differences between oncogenic BRAF and KRAS in colorectal cancer and find unexpected heterogeneity in a signalling pathway with fundamental relevance for cancer therapy.