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. von Furstenberg, Barry R. Stripp, Pankaj Agarwal, Alexander D. Borowsky, Robert D. Cardiff, Larry S. Barak, Marc G. Caron, H. Kim Lyerly, Joshua C. Snyder

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number5490
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Boone, P. G., Rochelle, L. K., Ginzel, J. D., Lubkov, V., Roberts, W. L., Nicholls, P. J., Bock, C., Flowers, M. L., von Furstenberg, R. J., Stripp, B. R., Agarwal, P., Borowsky, A. D., Cardiff, R. D., Barak, L. S., Caron, M. G., Lyerly, H. K., & Snyder, J. C. (2019). A cancer rainbow mouse for visualizing the functional genomics of oncogenic clonal expansion. Nature communications, 10(1), [5490]. https://doi.org/10.1038/s41467-019-13330-y