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

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.
Graphical Abstract
Highlights • Epithelial NOTCH1 signaling drives metastasis in serrated CRC • Poor-prognosis CRC subtypes CMS4/CRIS-B are controlled by NOTCH1 • TGF-β-mediated neutrophil infiltration is critical for NOTCH1-driven metastasis • Neutrophil targeting provides therapeutic opportunity in metastatic CRC
In a genetically engineered mouse model, Jackstadt et al. show that NOTCH1 activation drives metastasis in KRASG12D-driven serrated colorectal cancer (CRC) through TGFβ-dependent neutrophil recruitment. Thus, targeting neutrophil recruitment is a potential therapeutic approach in metastatic CRC.