Dipeptidase-1–knockout mice develop invasive tumors with features of microsatellite-unstable colorectal cancer

Dipeptidase-1 (DPEP1) is highly upregulated in colorectal cancer (CRC), with its enzymatic function linked to invasion and metastasis. More recently, DPEP1 was found to serve as a receptor for neutrophils when expressed by activated endothelial cells. It is unknown whether neutrophils bind to DPEP1-expressing CRC cells and whether this impacts features of CRC. Neutrophils have been shown to be tumor promoting in cancers including CRC, where they act to exclude CD8+ T cells. Herein, we show that neutrophils bind DPEP1-expressing CRC cells. In addition, DPEP1 is preferentially expressed in microsatellite-stable (MSS) CRCs, in which there are a paucity of CD8+ T cells, whereas DPEP1 is negatively correlated with microsatellite-unstable (MSI-H) CRCs, which are T cell rich and are more responsive to immunotherapy. Remarkably, carcinogen-treated Dpep1-null mice develop multiple, large, plaque-like, locally invasive adenocarcinomas and squamous cell cancers in the distal colon. These adenocarcinomas exhibit a marked reduction in neutrophils and an influx CD8+ T cells, along with reduced expression of mismatch repair proteins, consistent with features of MSI-H CRC. These results establish DPEP1's importance in maintaining MSS CRC and its ability to shape the tumor microenvironment.

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Publication Details

Journal
JCI Insight
Published
2025-04-03
DOI
https://doi.org/10.1172/jci.insight.186938
Citations
1
Primary Topic
Peptidase Inhibition and Analysis
Type
article
Field-Weighted Citation Impact
1.05
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article

Dipeptidase-1–knockout mice develop invasive tumors with features of microsatellite-unstable colorectal cancer

Robert A. Smith, Cody N. Heiser, Frank Revetta, Nicholas O. Markham et al.
1 citations
JCI Insight
Peptidase Inhibition and Analysis
1.05
article

Dipeptidase-1–knockout mice develop invasive tumors with features of microsatellite-unstable colorectal cancer

Robert A. Smith, Cody N. Heiser, Frank Revetta, Nicholas O. Markham, Annika Windon, Gregory D. Ayers, Robert J. Coffey, Chelsie K. Sievers, Alan J. Simmons, M. Kay Washington, Martha J. Shrubsole, Ken S. Lau, Yanwen Xu, Maria Johnson Irudayam, Matthew E. Bechard, Emily H. Green, Samuel T Ellis, Yu Wang, Qi Liu, Zheng Cao, Elizabeth Fisher, Ping Zhao, Sarah E Glass, Radhika Aramandla
article en
1 citations

Abstract

Dipeptidase-1 (DPEP1) is highly upregulated in colorectal cancer (CRC), with its enzymatic function linked to invasion and metastasis. More recently, DPEP1 was found to serve as a receptor for neutrophils when expressed by activated endothelial cells. It is unknown whether neutrophils bind to DPEP1-expressing CRC cells and whether this impacts features of CRC. Neutrophils have been shown to be tumor promoting in cancers including CRC, where they act to exclude CD8+ T cells. Herein, we show that neutrophils bind DPEP1-expressing CRC cells. In addition, DPEP1 is preferentially expressed in microsatellite-stable (MSS) CRCs, in which there are a paucity of CD8+ T cells, whereas DPEP1 is negatively correlated with microsatellite-unstable (MSI-H) CRCs, which are T cell rich and are more responsive to immunotherapy. Remarkably, carcinogen-treated Dpep1-null mice develop multiple, large, plaque-like, locally invasive adenocarcinomas and squamous cell cancers in the distal colon. These adenocarcinomas exhibit a marked reduction in neutrophils and an influx CD8+ T cells, along with reduced expression of mismatch repair proteins, consistent with features of MSI-H CRC. These results establish DPEP1's importance in maintaining MSS CRC and its ability to shape the tumor microenvironment.

JCI InsightVol. 10(9)
Vanderbilt University (US), Cornell University (US), VA Tennessee Valley Healthcare System (US), Biology of Infection (FR), Vanderbilt University Medical Center (US)
Zero hunger
Openalex Percentile: Top 24%
Peptidase Inhibition and Analysis
1.05
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