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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Jackstadt, R; van Hooff, SR; Leach, JD; Cortes-Lavaud, X; Lohuis, JO; Ridgway, RA; Wouters, VM; Roper, J; Kendall, TJ; Roxburgh, CS; Horgan, PG; Nixon, C; Nourse, C; Gunzer, M; Clark, W; Hedley, A; Yilmaz, OH; Rashid, M; Bailey, P; Biankin, AV; Campbell, AD; Adams, DJ; Barry, ST; Steele, CW; Medema, JP; Sansom, OJ

Published Date

  • September 16, 2019

Published In

Volume / Issue

  • 36 / 3

Start / End Page

  • 319 - 336.e7

PubMed ID

  • 31526760

Pubmed Central ID

  • PMC6853173

Electronic International Standard Serial Number (EISSN)

  • 1878-3686

Digital Object Identifier (DOI)

  • 10.1016/j.ccell.2019.08.003

Language

  • eng

Conference Location

  • United States