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

Jackstadt, R. et al. (2019) Epithelial NOTCH signaling rewires the tumor microenvironment of colorectal cancer to drive poor-prognosis subtypes and metastasis. Cancer Cell, 36(3), 319-336.e7. (doi: 10.1016/j.ccell.2019.08.003) (PMID:31526760)

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Abstract

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.

Item Type:Articles
Additional Information:We thank the Core Services and Advanced Technologies at the Cancer Research UK Beatson Institute (C596/A17169), and particularly the Biological Services Unit, Histology and Molecular Technologies. We are thankful to members of the Sansom lab for discussion and Catherine Winchester for editing the manuscript. O.J.S. and his lab members were supported by CRUK grants A26825, A28233, A23390, A21139, A12481 and A17196 and an ERC Starting Grant 311301. R.J. was supported by the Marie Skłodowska-Curie Actions postdoctoral fellowship (ERC 659666). J.D.L was supported by an MRC Clinical Research Training Fellowship (MR/N021800/1). J.P.M. and S.v.H. were supported by grants from the Dutch Cancer Society (Oncode, 10150, 10562).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Horgan, Professor Paul and Biankin, Professor Andrew and Nixon, Mr Colin and Roxburgh, Dr Campbell and Nourse, Dr Craig and Ridgway, Dr Rachel and Clark, Mr William and Bailey, Dr Peter and Leach, Joshua and Steele, Dr Colin and Sansom, Professor Owen and Campbell, Dr Andrew
Authors: Jackstadt, R., van Hooff, S. R., Leach, J. D., Cortes-Lavaud, X., Lohuis, J. O., Ridgway, R. A., Wouters, V. M., Roper, J., Kendall, T. J., Roxburgh, C. S., Horgan, P. G., Nixon, C., Nourse, C., Gunzer, M., Clark, W., Hedley, A., Yilmaz, O. H., Rashid, M., Bailey, P., Biankin, A. V., Campbell, A. D., Adams, D. J., Barry, S. T., Steele, C. W., Medema, J. P., and Sansom, O. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Cancer Cell
Publisher:Elsevier (Cell Press)
ISSN:1535-6108
ISSN (Online):1878-3686
Copyright Holders:Copyright © 2019 Jackstadt et al
First Published:First published in Cancer Cell 36:319-336
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
3019890ACRClerate: Colorectal Cancer Stratified Medicine NetworkOwen SansomCancer Research UK (CRUK)C7932/A26825CS - Beatson Institute for Cancer Research
716541Examining the relationship between KRAS mutation and immunotherapy resistance in colorectal cancerOwen SansomMedical Research Council (MRC)MR/N021800/1ICS - BEATSON INSTITUTE FOR CANCER RES.