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...

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Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2019
Materias:
Article
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
Descripción
Sumario: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.

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