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.
Reviewing Editor
- Chi Van Dang, University of Pennsylvania, United States
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).
Version history
- Received: August 4, 2016
- Accepted: January 9, 2017
- Accepted Manuscript published: January 10, 2017 (version 1)
- Version of Record published: January 26, 2017 (version 2)
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
-
- 3,473
- views
-
- 776
- downloads
-
- 71
- 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
- Genetics and Genomics
Relapse of acute myeloid leukemia (AML) is highly aggressive and often treatment refractory. We analyzed previously published AML relapse cohorts and found that 40% of relapses occur without changes in driver mutations, suggesting that non-genetic mechanisms drive relapse in a large proportion of cases. We therefore characterized epigenetic patterns of AML relapse using 26 matched diagnosis-relapse samples with ATAC-seq. This analysis identified a relapse-specific chromatin accessibility signature for mutationally stable AML, suggesting that AML undergoes epigenetic evolution at relapse independent of mutational changes. Analysis of leukemia stem cell (LSC) chromatin changes at relapse indicated that this leukemic compartment underwent significantly less epigenetic evolution than non-LSCs, while epigenetic changes in non-LSCs reflected overall evolution of the bulk leukemia. Finally, we used single-cell ATAC-seq paired with mitochondrial sequencing (mtscATAC) to map clones from diagnosis into relapse along with their epigenetic features. We found that distinct mitochondrially-defined clones exhibit more similar chromatin accessibility at relapse relative to diagnosis, demonstrating convergent epigenetic evolution in relapsed AML. These results demonstrate that epigenetic evolution is a feature of relapsed AML and that convergent epigenetic evolution can occur following treatment with induction chemotherapy.
-
- Cancer Biology
- Cell Biology
Rapid recovery of proteasome activity may contribute to intrinsic and acquired resistance to FDA-approved proteasome inhibitors. Previous studies have demonstrated that the expression of proteasome genes in cells treated with sub-lethal concentrations of proteasome inhibitors is upregulated by the transcription factor Nrf1 (NFE2L1), which is activated by a DDI2 protease. Here, we demonstrate that the recovery of proteasome activity is DDI2-independent and occurs before transcription of proteasomal genes is upregulated but requires protein translation. Thus, mammalian cells possess an additional DDI2 and transcription-independent pathway for the rapid recovery of proteasome activity after proteasome inhibition.
