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

被引：335

作者：

Jackstadt, Rene ^{[1
]}

van Hooff, Sander R. ^{[2
,3
]}

Leach, Joshua D. ^{[1
,4
]}

Cortes-Lavaud, Xabier ^{[1
]}

Lohuis, Jeroen O. ^{[1
]}

Ridgway, Rachel A. ^{[1
]}

Wouters, Valerie M. ^{[2
,3
]}

Roper, Jatin ^{[5
]}

Kendall, Timothy J. ^{[6
]}

Roxburgh, Campbell S. ^{[7
]}

Horgan, Paul G. ^{[7
]}

Nixon, Colin ^{[1
]}

Nourse, Craig ^{[1
]}

Gunzer, Matthias ^{[8
]}

Clark, William ^{[1
]}

Hedley, Ann ^{[1
]}

Yilmaz, Omer H. ^{[9
,10
]}

Rashid, Mamunur ^{[11
]}

Bailey, Peter ^{[4
]}

Biankin, Andrew, V ^{[4
]}

Campbell, Andrew D. ^{[1
]}

Adams, David J. ^{[11
]}

Barry, Simon T. ^{[12
]}

Steele, Colin W. ^{[1
,4
]}

Medema, Jan Paul ^{[2
,3
]}

Sansom, Owen J. ^{[1
,4
]}

机构：

[1] Canc Res UK Beatson Inst, Glasgow, Lanark, Scotland

[2] Univ Amsterdam, Acad Med Ctr, CEMM, Lab Expt Oncol & Radiobiol LEXOR, Amsterdam, Netherlands

[3] Oncode Inst, Amsterdam, Netherlands

[4] Univ Glasgow, Inst Canc Sci, Garscube Estate, Glasgow, Lanark, Scotland

[5] Duke Univ, Dept Med, Div Gastroenterol, Durham, NC USA

[6] Univ Edinburgh, Ctr Inflammat Res, Div Pathol, Edinburgh, Midlothian, Scotland

[7] Univ Glasgow, Acad Unit Surg, Sch Med, Glasgow, Lanark, Scotland

[8] Univ Duisburg Essen, Univ Hosp, Inst Expt Immunol & Imaging, Essen, Germany

[9] Tufts Med Ctr, Div Gastroenterol, Boston, MA 02111 USA

[10] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

[11] Wellcome Sanger Inst, Wellcome Genome Campus, Cambridge, England

[12] AstraZeneca, Oncol R&D, Biosci, Cambridge, England

来源：

CANCER CELL | 2019年 / 36卷 / 03期

基金：

欧洲研究理事会;

关键词：

CONSENSUS MOLECULAR SUBTYPES; MOUSE MODELS; COLON-CANCER; READ ALIGNMENT; COPY NUMBER; STEM-CELLS; WNT; INHIBITION; EXPRESSION; IMMUNE;

D O I：

10.1016/j.ccell.2019.08.003

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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) beta-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.

引用

页码：319 / +

页数：25

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