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

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

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

351 Citations (Scopus)

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. In a genetically engineered mouse model, Jackstadt et al. show that NOTCH1 activation drives metastasis in KRAS^G12D-driven serrated colorectal cancer (CRC) through TGFβ-dependent neutrophil recruitment. Thus, targeting neutrophil recruitment is a potential therapeutic approach in metastatic CRC.

Original language	English
Pages (from-to)	319-336.e7
Journal	Cancer Cell
Volume	36
Issue number	3
DOIs	https://doi.org/10.1016/j.ccell.2019.08.003
Publication status	Published - 16 Sept 2019
Externally published	Yes

Keywords

CRC intrinsic subtypes (CRIS)
NOTCH1
TGF-β
colorectal cancer (CRC)
consensus molecular subtype (CMS)
metastasis
molecular subtyping
neutrophils
serrated CRC
tumor microenviroment (TME)

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10.1016/j.ccell.2019.08.003

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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. J., 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, 36(3), 319-336.e7. https://doi.org/10.1016/j.ccell.2019.08.003

@article{1c8d0cc036df487aa853baf8fac26eae,

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 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. In a genetically engineered mouse model, Jackstadt et al. show that NOTCH1 activation drives metastasis in KRASG12D-driven serrated colorectal cancer (CRC) through TGFβ-dependent neutrophil recruitment. Thus, targeting neutrophil recruitment is a potential therapeutic approach in metastatic CRC.",

keywords = "CRC intrinsic subtypes (CRIS), NOTCH1, TGF-β, colorectal cancer (CRC), consensus molecular subtype (CMS), metastasis, molecular subtyping, neutrophils, serrated CRC, tumor microenviroment (TME)",

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, \{Val{\'e}rie M.\} and Jatin Roper and Kendall, \{Timothy J.\} 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.\}",

note = "Publisher Copyright: {\textcopyright} 2019 The Authors",

year = "2019",

month = sep,

day = "16",

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

language = "English",

volume = "36",

pages = "319--336.e7",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "3",

}

Jackstadt, R, van Hooff, SR, Leach, JD, Cortes-Lavaud, X, Lohuis, JO, Ridgway, RA, Wouters, VM, Roper, J, Kendall, TJ, 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, vol. 36, no. 3, pp. 319-336.e7. 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, Valérie M.

AU - Roper, Jatin

AU - Kendall, Timothy J.

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 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. In a genetically engineered mouse model, Jackstadt et al. show that NOTCH1 activation drives metastasis in KRASG12D-driven serrated colorectal cancer (CRC) through TGFβ-dependent neutrophil recruitment. Thus, targeting neutrophil recruitment is a potential therapeutic approach in metastatic CRC.

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 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. In a genetically engineered mouse model, Jackstadt et al. show that NOTCH1 activation drives metastasis in KRASG12D-driven serrated colorectal cancer (CRC) through TGFβ-dependent neutrophil recruitment. Thus, targeting neutrophil recruitment is a potential therapeutic approach in metastatic CRC.

KW - CRC intrinsic subtypes (CRIS)

KW - NOTCH1

KW - TGF-β

KW - colorectal cancer (CRC)

KW - consensus molecular subtype (CMS)

KW - metastasis

KW - molecular subtyping

KW - neutrophils

KW - serrated CRC

KW - tumor microenviroment (TME)

UR - https://www.scopus.com/pages/publications/85071623617

U2 - 10.1016/j.ccell.2019.08.003

DO - 10.1016/j.ccell.2019.08.003

M3 - Article

C2 - 31526760

AN - SCOPUS:85071623617

SN - 1535-6108

VL - 36

SP - 319-336.e7

JO - Cancer Cell

JF - Cancer Cell

IS - 3

ER -

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

Abstract

Keywords

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