Epithelial NOTCH Signaling Rewires the Tumor Microenvironment of Colorectal Cancer to Drive Poor-Prognosis Subtypes and Metastasis
Epithelial NOTCH Signaling Rewires the Tumor Microenvironment of Colorectal Cancer to Drive Poor-Prognosis Subtypes and Metastasis
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DOI：
10.1016/j.ccell.2019.08.003
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发表时间：
2019-09-16
期刊：
影响因子：
50.3
通讯作者：
Sansom, Owen J.
中科院分区：
文献类型：
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作者：
Jackstadt, Rene;van Hooff, Sander R.;Sansom, Owen J.
结直肠癌（CRC）的转移过程尚未完全了解，缺乏有效的治疗方法。我们发现，在Kras（G12 D）驱动的锯齿状癌中，小鼠肠上皮中NOTCH 1信号传导的激活导致高度渗透性转移（100%转移;具有>80%的肝转移）。转录谱显示，上皮NOTCH 1信号传导产生了一种肿瘤微环境（TME），让人想起预后不良的人类CRC亚型（CMS 4和CRIS-B），并通过转化生长因子（TGF）β依赖性中性粒细胞募集驱动转移。重要的是，用临床相关的治疗剂抑制这种募集阻断了转移。我们认为NOTCH 1信号是CRC进展的关键，应在临床上加以利用。
The metastatic process of colorectal cancer (CRC) is not fully understood and effective therapies are lacking. We show that activation of NOTCH1 signaling in the murine intestinal epithelium leads to highly penetrant metastasis (100% metastasis; with >80% liver metastases) in Kras(G12D)-driven serrated cancer. Transcriptional profiling reveals that epithelial NOTCH1 signaling creates a tumor microenvironment (TME) reminiscent of poorly prognostic human CRC subtypes (CMS4 and CRIS-B), and drives metastasis through transforming growth factor (TGF) beta-dependent neutrophil recruitment. Importantly, inhibition of this recruitment with clinically relevant therapeutic agents blocks metastasis. We propose that NOTCH1 signaling is key to CRC progression and should be exploited clinically.