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

Publication date: 16 September 2019Source: Cancer Cell, Volume 36, Issue 3Author(s): 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. BiankinSummaryThe 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.Graphical Abstract
Source: Cancer Cell - Category: Cancer & Oncology Source Type: research