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

Autor:	Jackstadt R; Cancer Research UK Beatson Institute, Glasgow, UK., van Hooff SR; 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., Leach JD; Cancer Research UK Beatson Institute, Glasgow, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK., Cortes-Lavaud X; Cancer Research UK Beatson Institute, Glasgow, UK., Lohuis JO; Cancer Research UK Beatson Institute, Glasgow, UK., Ridgway RA; Cancer Research UK Beatson Institute, Glasgow, UK., Wouters VM; 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., Roper J; Department of Medicine, Division of Gastroenterology, Duke University, Durham, NC, USA., Kendall TJ; Division of Pathology/Centre for Inflammation Research, University of Edinburgh, UK., Roxburgh CS; Academic Unit of Surgery, School of Medicine, University of Glasgow, Glasgow, UK., Horgan PG; Academic Unit of Surgery, School of Medicine, University of Glasgow, Glasgow, UK., Nixon C; Cancer Research UK Beatson Institute, Glasgow, UK., Nourse C; Cancer Research UK Beatson Institute, Glasgow, UK., Gunzer M; Institute for Experimental Immunology and Imaging, University Hospital, University Duisburg-Essen, Essen, Germany., Clark W; Cancer Research UK Beatson Institute, Glasgow, UK., Hedley A; Cancer Research UK Beatson Institute, Glasgow, UK., Yilmaz OH; Division of Gastroenterology, Tufts Medical Center, Boston, MA, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA, USA., Rashid M; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK., Bailey P; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK., Biankin AV; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK., Campbell AD; Cancer Research UK Beatson Institute, Glasgow, UK., Adams DJ; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK., Barry ST; Bioscience, Oncology R&D, AstraZeneca, Cambridge, UK., Steele CW; Cancer Research UK Beatson Institute, Glasgow, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK., Medema JP; 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., Sansom OJ; 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.
Jazyk:	angličtina
Zdroj:	Cancer cell [Cancer Cell] 2019 Sep 16; Vol. 36 (3), pp. 319-336.e7.
DOI:	10.1016/j.ccell.2019.08.003
Abstrakt:	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. (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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