[PDF][PDF] Epithelial NOTCH signaling rewires the tumor microenvironment of colorectal cancer to drive poor-prognosis subtypes and metastasis

R Jackstadt, SR van Hooff, JD Leach, X Cortes-Lavaud… - Cancer cell, 2019 - cell.com
R Jackstadt, SR van Hooff, JD Leach, X Cortes-Lavaud, JO Lohuis, RA Ridgway…
Cancer cell, 2019cell.com
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 …
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.
cell.com