Abstract
AbstractField cancerization is a premalignant process marked by clones of oncogenic mutations spreading through the epithelium. The timescales of intestinal field cancerization can be variable and the mechanisms driving the rapid spread of oncogenic clones are unknown. Here we use a Cancer rainbow (Crainbow) modelling system for fluorescently barcoding somatic mutations and directly visualizing the clonal expansion and spread of oncogenes. Crainbow shows that mutations of ß-catenin (Ctnnb1) within the intestinal stem cell results in widespread expansion of oncogenes during perinatal development but not in adults. In contrast, mutations that extrinsically disrupt the stem cell microenvironment can spread in adult intestine without delay. We observe the rapid spread of premalignant clones in Crainbow mice expressing oncogenic Rspondin-3 (RSPO3), which occurs by increasing crypt fission and inhibiting crypt fixation. Crainbow modelling provides insight into how somatic mutations rapidly spread and a plausible mechanism for predetermining the intratumor heterogeneity found in colon cancers.
Funder
U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development
U.S. Department of Health & Human Services | NIH | National Cancer Institute
Duke Surgery Start-up Funds Duke Surgery Gardner Award
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
Reference66 articles.
1. Curtius, K., Wright, N. A. & Graham, T. A. An evolutionary perspective on field cancerization. Nat. Rev. Cancer 18, 19–32 (2018).
2. Braakhuis, B. J., Tabor, M. P., Kummer, J. A., Leemans, C. R. & Brakenhoff, R. H. A genetic explanation of Slaughter’s concept of field cancerization: evidence and clinical implications. Cancer Res. 63, 1727–1730 (2003).
3. Sottoriva, A. et al. A Big Bang model of human colorectal tumor growth. Nat. Genet. 47, 209–216 (2015).
4. Galandiuk, S. et al. Field cancerization in the intestinal epithelium of patients with Crohn’s ileocolitis. Gastroenterology 142, 855–864 e858 (2012).
5. Jothy, S. et al. Field effect of human colon carcinoma on normal mucosa: relevance of carcinoembryonic antigen expression. Tumour Biol. 17, 58–64 (1996).
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