A cancer rainbow mouse for visualizing the functional genomics of oncogenic clonal expansion

Peter G. Boone, Lauren K. Rochelle, Joshua D. Ginzel, Veronica Lubkov, Wendy L. Roberts, P. J. Nicholls, Cheryl Bock, Mei Lang Flowers, Richard J. Furstenberg, Barry R. Stripp, Pankaj Agarwal, Alexander D. Borowsky, Robert D. Cardiff, Larry S. Barak, Marc G. Caron, H. Kim Lyerly and Joshua C. Snyder ()
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Peter G. Boone: Duke University School of Medicine
Lauren K. Rochelle: Duke University School of Medicine
Joshua D. Ginzel: Duke University School of Medicine
Veronica Lubkov: Duke University School of Medicine
Wendy L. Roberts: Duke University School of Medicine
P. J. Nicholls: Duke University School of Medicine
Cheryl Bock: Duke Cancer Institute
Mei Lang Flowers: Duke Cancer Institute
Richard J. Furstenberg: Duke University School of Medicine
Barry R. Stripp: Cedars-Sinai Medical Center
Pankaj Agarwal: Duke University School of Medicine
Alexander D. Borowsky: University of California-Davis
Robert D. Cardiff: University of California-Davis
Larry S. Barak: Duke University School of Medicine
Marc G. Caron: Duke University School of Medicine
H. Kim Lyerly: Duke University School of Medicine
Joshua C. Snyder: Duke University School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract Field 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.

Date: 2019
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DOI: 10.1038/s41467-019-13330-y

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