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Epithelial NOTCH Signaling Rewires the Tumor Microenvironment of Colorectal Cancer to Drive Poor-Prognosis Subtypes and Metastasis
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 se...
| Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Formato: | Online Artículo Texto |
| Lenguaje: | English |
| Publicado: |
Cell Press
2019
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| Materias: | |
| Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853173/ https://www.ncbi.nlm.nih.gov/pubmed/31526760 http://dx.doi.org/10.1016/j.ccell.2019.08.003 |
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| author | Jackstadt, Rene van Hooff, Sander R. Leach, Joshua D. Cortes-Lavaud, Xabier Lohuis, Jeroen O. Ridgway, Rachel A. Wouters, Valérie M. Roper, Jatin Kendall, Timothy J. Roxburgh, Campbell S. Horgan, Paul G. Nixon, Colin Nourse, Craig Gunzer, Matthias Clark, William Hedley, Ann Yilmaz, Omer H. Rashid, Mamunur Bailey, Peter Biankin, Andrew V. Campbell, Andrew D. Adams, David J. Barry, Simon T. Steele, Colin W. Medema, Jan Paul Sansom, Owen J. |
| author_facet | Jackstadt, Rene van Hooff, Sander R. Leach, Joshua D. Cortes-Lavaud, Xabier Lohuis, Jeroen O. Ridgway, Rachel A. Wouters, Valérie M. Roper, Jatin Kendall, Timothy J. Roxburgh, Campbell S. Horgan, Paul G. Nixon, Colin Nourse, Craig Gunzer, Matthias Clark, William Hedley, Ann Yilmaz, Omer H. Rashid, Mamunur Bailey, Peter Biankin, Andrew V. Campbell, Andrew D. Adams, David J. Barry, Simon T. Steele, Colin W. Medema, Jan Paul Sansom, Owen J. |
| author_sort | Jackstadt, Rene |
| collection | PubMed |
| description | 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. |
| format | Online Article Text |
| id | pubmed-6853173 |
| institution | National Center for Biotechnology Information |
| language | English |
| publishDate | 2019 |
| publisher | Cell Press |
| record_format | MEDLINE/PubMed |
| spelling | pubmed-68531732019-11-20 Epithelial NOTCH Signaling Rewires the Tumor Microenvironment of Colorectal Cancer to Drive Poor-Prognosis Subtypes and Metastasis Jackstadt, Rene van Hooff, Sander R. Leach, Joshua D. Cortes-Lavaud, Xabier Lohuis, Jeroen O. Ridgway, Rachel A. Wouters, Valérie M. Roper, Jatin Kendall, Timothy J. Roxburgh, Campbell S. Horgan, Paul G. Nixon, Colin Nourse, Craig Gunzer, Matthias Clark, William Hedley, Ann Yilmaz, Omer H. Rashid, Mamunur Bailey, Peter Biankin, Andrew V. Campbell, Andrew D. Adams, David J. Barry, Simon T. Steele, Colin W. Medema, Jan Paul Sansom, Owen J. Cancer Cell 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 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. Cell Press 2019-09-16 /pmc/articles/PMC6853173/ /pubmed/31526760 http://dx.doi.org/10.1016/j.ccell.2019.08.003 Text en © 2019 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
| spellingShingle | Article Jackstadt, Rene van Hooff, Sander R. Leach, Joshua D. Cortes-Lavaud, Xabier Lohuis, Jeroen O. Ridgway, Rachel A. Wouters, Valérie M. Roper, Jatin Kendall, Timothy J. Roxburgh, Campbell S. Horgan, Paul G. Nixon, Colin Nourse, Craig Gunzer, Matthias Clark, William Hedley, Ann Yilmaz, Omer H. Rashid, Mamunur Bailey, Peter Biankin, Andrew V. Campbell, Andrew D. Adams, David J. Barry, Simon T. Steele, Colin W. Medema, Jan Paul Sansom, Owen J. Epithelial NOTCH Signaling Rewires the Tumor Microenvironment of Colorectal Cancer to Drive Poor-Prognosis Subtypes and Metastasis |
| title | Epithelial NOTCH Signaling Rewires the Tumor Microenvironment of Colorectal Cancer to Drive Poor-Prognosis Subtypes and Metastasis |
| title_full | Epithelial NOTCH Signaling Rewires the Tumor Microenvironment of Colorectal Cancer to Drive Poor-Prognosis Subtypes and Metastasis |
| title_fullStr | Epithelial NOTCH Signaling Rewires the Tumor Microenvironment of Colorectal Cancer to Drive Poor-Prognosis Subtypes and Metastasis |
| title_full_unstemmed | Epithelial NOTCH Signaling Rewires the Tumor Microenvironment of Colorectal Cancer to Drive Poor-Prognosis Subtypes and Metastasis |
| title_short | Epithelial NOTCH Signaling Rewires the Tumor Microenvironment of Colorectal Cancer to Drive Poor-Prognosis Subtypes and Metastasis |
| title_sort | epithelial notch signaling rewires the tumor microenvironment of colorectal cancer to drive poor-prognosis subtypes and metastasis |
| topic | Article |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853173/ https://www.ncbi.nlm.nih.gov/pubmed/31526760 http://dx.doi.org/10.1016/j.ccell.2019.08.003 |
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