英国格拉斯哥大学Owen J. Sansom研究团队上皮中的NOTCH信号重塑结直肠癌（CRC）的肿瘤微环境，以驱动预后差的亚型产生与肿瘤转移。2019年9月16日出版的《癌细胞》发表了这一成果。

研究人员发现在小鼠肠上皮中激活NOTCH1信号通路导致KrasG12D驱动的肿瘤发生产生中高度渗透性转移（100％转移；超过80％肝转移）。转录分析显示上皮NOTCH1信号产生肿瘤微环境（TME），这让研究人员联想到预后不良的人类CRC亚型（CMS4和CRIS-B），并通过转化生长因子（TGF）β依赖性中性粒细胞招募来驱动转移。重要的是，用临床相关治疗剂抑制这种招募可以阻止转移。 研究人员认为NOTCH1信号是CRC进展的关键，应该在临床上加以利用。

研究人员介绍，CRC的转移过程尚不完全清楚，并且缺乏有效的治疗方法。

附：英文原文

Title: Epithelial NOTCH Signaling Rewires the Tumor Microenvironment of Colorectal Cancer to Drive Poor-Prognosis Subtypes and Metastasis

Author: Rene Jackstadt, Sander R. van Hooff, Joshua D. Leach, Xabier Cortes-Lavaud, Jeroen O. Lohuis, Rachel A. Ridgway, Valérie M. Wouters, Jatin Roper, Timothy J. Kendall, Campbell S. Roxburgh, Paul G. Horgan, Colin Nixon, Craig Nourse, Matthias Gunzer, William Clark, Ann Hedley, Omer H. Yilmaz, Mamunur Rashid, Peter Bailey, Andrew V. Biankin, Andrew D. Campbell, David J. Adams, Simon T. Barry, Colin W. Steele, Jan Paul Medema, Owen J. Sansom

Issue&Volume: Volume 36 Issue 3

Summary: 

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 KrasG12D-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) β-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.

DOI: 10.1016/j.ccell.2019.08.003

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(19)30371-X