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; Valerie M Wouters; Jatin Roper; Tim 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

Rene Jackstadt, Sander R. van Hooff, Joshua D Leach, Xabier Cortes-Lavaud, Jeroen O Lohuis, Rachel A Ridgway, Valerie M Wouters, Jatin Roper, Tim 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 BiankinAndrew D Campbell, David J Adams, Simon T Barry, Colin W Steele, Jan Paul Medema, Owen J Sansom

Research output: Contribution to journal › Article › peer-review

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 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.

Original language	English
Journal	Cancer Cell
DOIs	https://doi.org/10.1016/j.ccell.2019.08.003
Publication status	Published - 16 Sept 2019

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10.1016/j.ccell.2019.08.003

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This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Final published version, 225 KBLicence: Creative Commons: Attribution (CC-BY)

https://www.sciencedirect.com/science/article/pii/S153561081930371X

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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., Roxburgh, C. S., Horgan, P. G., Nixon, C., Nourse, C., Gunzer, M., Clark, W., Hedley, A., Yilmaz, O. H., Rashid, M., Bailey, P., ... Sansom, O. J. (2019). Epithelial NOTCH signaling rewires the tumor microenvironment of colorectal cancer to drive poor-prognosis subtypes and metastasis. Cancer Cell. https://doi.org/10.1016/j.ccell.2019.08.003

@article{6c6885373fcd48a4876a956929e2508e,

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

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 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.",

author = "Rene Jackstadt and \{van Hooff\}, \{Sander R.\} and Leach, \{Joshua D\} and Xabier Cortes-Lavaud and Lohuis, \{Jeroen O\} and Ridgway, \{Rachel A\} and Wouters, \{Valerie M\} and Jatin Roper and Tim Kendall and Roxburgh, \{Campbell S\} and Horgan, \{Paul G\} and Colin Nixon and Craig Nourse and Matthias Gunzer and William Clark and Ann Hedley and Yilmaz, \{Omer H\} and Mamunur Rashid and Peter Bailey and Biankin, \{Andrew V\} and Campbell, \{Andrew D\} and Adams, \{David J\} and Barry, \{Simon T\} and Steele, \{Colin W\} and Medema, \{Jan Paul\} and Sansom, \{Owen J\}",

year = "2019",

month = sep,

day = "16",

doi = "10.1016/j.ccell.2019.08.003",

language = "English",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

}

Jackstadt, R, van Hooff, SR, Leach, JD, Cortes-Lavaud, X, Lohuis, JO, Ridgway, RA, Wouters, VM, Roper, J, Kendall, T, Roxburgh, CS, Horgan, PG, Nixon, C, Nourse, C, Gunzer, M, Clark, W, Hedley, A, Yilmaz, OH, Rashid, M, Bailey, P, Biankin, AV, Campbell, AD, Adams, DJ, Barry, ST, Steele, CW, Medema, JP & Sansom, OJ 2019, 'Epithelial NOTCH signaling rewires the tumor microenvironment of colorectal cancer to drive poor-prognosis subtypes and metastasis', Cancer Cell. https://doi.org/10.1016/j.ccell.2019.08.003

TY - JOUR

T1 - Epithelial NOTCH signaling rewires the tumor microenvironment of colorectal cancer to drive poor-prognosis subtypes and metastasis

AU - Jackstadt, Rene

AU - van Hooff, Sander R.

AU - Leach, Joshua D

AU - Cortes-Lavaud, Xabier

AU - Lohuis, Jeroen O

AU - Ridgway, Rachel A

AU - Wouters, Valerie M

AU - Roper, Jatin

AU - Kendall, Tim

AU - Roxburgh, Campbell S

AU - Horgan, Paul G

AU - Nixon, Colin

AU - Nourse, Craig

AU - Gunzer, Matthias

AU - Clark, William

AU - Hedley, Ann

AU - Yilmaz, Omer H

AU - Rashid, Mamunur

AU - Bailey, Peter

AU - Biankin, Andrew V

AU - Campbell, Andrew D

AU - Adams, David J

AU - Barry, Simon T

AU - Steele, Colin W

AU - Medema, Jan Paul

AU - Sansom, Owen J

PY - 2019/9/16

Y1 - 2019/9/16

N2 - 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 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.

AB - 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 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.

U2 - 10.1016/j.ccell.2019.08.003

DO - 10.1016/j.ccell.2019.08.003

M3 - Article

SN - 1535-6108

JO - Cancer Cell

JF - Cancer Cell

ER -

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

Abstract

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