BRAFV600E cooperates with CDX2 inactivation to promote serrated colorectal tumorigenesis
- University of Michigan, United States
- Hiroshima University, Japan
- University of Utah Medical Schoo, United States
Abstract
While 20-30% of colorectal cancers (CRCs) may arise from precursors with serrated glands, only 8-10% of CRCs manifest serrated morphology at diagnosis. Markers for distinguishing CRCs arising from 'serrated' versus 'conventional adenoma' precursors are lacking. We studied 36 human serrated CRCs and found CDX2 loss or BRAF mutations in ~60% of cases and often together (p= .04). CDX2Null/BRAFV600E expression in adult mouse intestinal epithelium led to serrated morphology tumors (including carcinomas) and BRAFV600E potently interacted with CDX2 silencing to alter gene expression. Like human serrated lesions, CDX2Null/BRAFV600E-mutant epithelium expressed gastric markers. Organoids from CDX2Null/BRAFV600E-mutant colon epithelium showed serrated features, and partially recapitulated the gene expression pattern in mouse colon tissues. We present a novel mouse tumor model based on signature defects seen in many human serrated CRCs - CDX2 loss and BRAFV600E. The mouse intestinal tumors show significant phenotypic similarities to human serrated CRCs and inform about serrated CRC pathogenesis.
Data availability
-
Colon tumor samples from mice with Braf V600E, Cdx2-/-, or both, as well as control colon, and tumors from Apc-/- mice.Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE84650).
Article and author information
Author details
Funding
National Institutes of Health (R01CA082223)
- Eric R Fearon
National Institutes of Health (R01CA176839)
- Martin McMahon
National Institutes of Health (P30CA046592)
- Eric R Fearon
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Procedures involving mice for the research described herein have been approved by the University of Michigan's Institutional Animal Care and Use Committee (PRO00005075) and were carried out according to Michigan state and US federal regulations.
Human subjects: The colorectal cancers were studied in accordance with the Ethical Guidelines for Human Genome/Gene Research enacted by the Japanese Government. We also studied human benign serrated colorectal lesions obtained from the University of Michigan tissue procurement service through an Institutional Review Board-approved protocol (#00058054).
Copyright
© 2017, Sakamoto et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 3,680
- views
-
- 798
- downloads
-
- 76
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
BRAFV600E cooperates with CDX2 inactivation to promote serrated colorectal tumorigenesis
eLife 6:e20331.
https://doi.org/10.7554/eLife.20331
Further reading
-
- Cancer Biology
- Immunology and Inflammation
In this study, we present a proof-of-concept classical vaccination experiment that validates the in silico identification of tumor neoantigens (TNAs) using a machine learning-based platform called NAP-CNB. Unlike other TNA predictors, NAP-CNB leverages RNA-seq data to consider the relative expression of neoantigens in tumors. Our experiments show the efficacy of NAP-CNB. Predicted TNAs elicited potent antitumor responses in mice following classical vaccination protocols. Notably, optimal antitumor activity was observed when targeting the antigen with higher expression in the tumor, which was not the most immunogenic. Additionally, the vaccination combining different neoantigens resulted in vastly improved responses compared to each one individually, showing the worth of multiantigen-based approaches. These findings validate NAP-CNB as an innovative TNA identification platform and make a substantial contribution to advancing the next generation of personalized immunotherapies.
-
- Cancer Biology
Most human pancreatic ductal adenocarcinoma (PDAC) are not infiltrated with cytotoxic T cells and are highly resistant to immunotherapy. Over 90% of PDAC have oncogenic KRAS mutations, and phosphoinositide 3-kinases (PI3Ks) are direct effectors of KRAS. Our previous study demonstrated that ablation of Pik3ca in KPC (KrasG12D; Trp53R172H; Pdx1-Cre) pancreatic cancer cells induced host T cells to infiltrate and completely eliminate the tumors in a syngeneic orthotopic implantation mouse model. Now, we show that implantation of Pik3ca−/− KPC (named αKO) cancer cells induces clonal enrichment of cytotoxic T cells infiltrating the pancreatic tumors. To identify potential molecules that can regulate the activity of these anti-tumor T cells, we conducted an in vivo genome-wide gene-deletion screen using αKO cells implanted in the mouse pancreas. The result shows that deletion of propionyl-CoA carboxylase subunit B gene (Pccb) in αKO cells (named p-αKO) leads to immune evasion, tumor progression, and death of host mice. Surprisingly, p-αKO tumors are still infiltrated with clonally enriched CD8+ T cells but they are inactive against tumor cells. However, blockade of PD-L1/PD1 interaction reactivated these clonally enriched T cells infiltrating p-αKO tumors, leading to slower tumor progression and improve survival of host mice. These results indicate that Pccb can modulate the activity of cytotoxic T cells infiltrating some pancreatic cancers and this understanding may lead to improvement in immunotherapy for this difficult-to-treat cancer.
