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

Cancer Cell. 2019 Sep 16;36(3):319-336.e7. doi: 10.1016/j.ccell.2019.08.003.

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.

Keywords: CRC intrinsic subtypes (CRIS); NOTCH1; TGF-β; colorectal cancer (CRC); consensus molecular subtype (CMS); metastasis; molecular subtyping; neutrophils; serrated CRC; tumor microenviroment (TME).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / immunology
  • Colorectal Neoplasms / mortality
  • Colorectal Neoplasms / pathology*
  • Datasets as Topic
  • Disease Models, Animal
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / pathology
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / immunology
  • Liver Neoplasms / secondary
  • Male
  • Mice
  • Mutation
  • Neutrophil Activation / drug effects
  • Neutrophil Activation / genetics
  • Neutrophils / immunology
  • Prognosis
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Survival Analysis
  • Transforming Growth Factor beta / antagonists & inhibitors
  • Transforming Growth Factor beta / metabolism
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / immunology

Substances

  • KRAS protein, human
  • NOTCH1 protein, human
  • Notch1 protein, mouse
  • Receptor, Notch1
  • Transforming Growth Factor beta
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)