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. BiankinAndrew D. Campbell, David J. Adams, Simon T. Barry, Colin W. Steele, Jan Paul Medema, Owen J. Sansom

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

171 Citaten (Scopus)

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)319-336.e7
TijdschriftCancer Cell
Volume36
Nummer van het tijdschrift3
DOI's
StatusGepubliceerd - 16 sep. 2019
Extern gepubliceerdJa

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