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  • 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.

Cancer cell (2019-09-19)
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
PMID31526760
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description
A2547
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Monoclonal Anti-Actin, α-Smooth Muscle, clone 1A4, ascites fluid
R0901
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RNAlater®, Stabilize and protect RNA with immediate RNase inactivation
T5648
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