Epithelial NOTCH Signaling Rewires the Tumor Microenvironment of Colorectal Cancer to Drive Poor-Prognosis Subtypes and Metastasis
Name
1-s2.0-S153561081930371X-main.pdf
Description
Published version
Size
7.12 MB
Format
Unknown
Checksum (MD5)
a01c4658ecba7be84641305680261542
Author(s)
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.
Date Issued
September 2019
Journal
Cancer Cell
Publisher
Elsevier BV
Version
Final published version
Abstract
© 2019 The Authors 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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Terms of Use
Creative Commons Attribution 4.0 International license
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1016/j.ccell.2019.08.003
