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

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

doi:10.1016/j.ccell.2019.08.003

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.

Authors

Rene Jackstadt¹, Sander R van Hooff², Joshua D Leach³, Xabier Cortes-Lavaud¹, Jeroen O Lohuis¹, Rachel A Ridgway¹, Valérie M Wouters², Jatin Roper⁴, Timothy J Kendall⁵, Campbell S Roxburgh⁶, Paul G Horgan⁶, Colin Nixon¹, Craig Nourse¹, Matthias Gunzer⁷, William Clark¹, Ann Hedley¹, Omer H Yilmaz⁸, Mamunur Rashid⁹, Peter Bailey¹⁰, Andrew V Biankin¹⁰, Andrew D Campbell¹, David J Adams⁹, Simon T Barry¹¹, Colin W Steele³, Jan Paul Medema², Owen J Sansom¹²

Affiliations

¹ Cancer Research UK Beatson Institute, Glasgow, UK.
² Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands.
³ Cancer Research UK Beatson Institute, Glasgow, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK.
⁴ Department of Medicine, Division of Gastroenterology, Duke University, Durham, NC, USA.
⁵ Division of Pathology/Centre for Inflammation Research, University of Edinburgh, UK.
⁶ Academic Unit of Surgery, School of Medicine, University of Glasgow, Glasgow, UK.
⁷ Institute for Experimental Immunology and Imaging, University Hospital, University Duisburg-Essen, Essen, Germany.
⁸ Division of Gastroenterology, Tufts Medical Center, Boston, MA, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
⁹ Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
¹⁰ Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK.
¹¹ Bioscience, Oncology R&D, AstraZeneca, Cambridge, UK.
¹² Cancer Research UK Beatson Institute, Glasgow, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK. Electronic address: o.sansom@beatson.gla.ac.uk.

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 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 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)

Abstract

Publication types

MeSH terms

Substances

Grants and funding