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

Autor: Boone PG; Division of Surgical Sciences, Department of Surgery, Duke University School of Medicine, Durham, NC, USA.; Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA., Rochelle LK; Division of Surgical Sciences, Department of Surgery, Duke University School of Medicine, Durham, NC, USA.; Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA., Ginzel JD; Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA., Lubkov V; Division of Surgical Sciences, Department of Surgery, Duke University School of Medicine, Durham, NC, USA.; Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA., Roberts WL; Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA., Nicholls PJ; Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA., Bock C; Transgenic Mouse Facility, Duke Cancer Institute, Durham, NC, USA., Flowers ML; Transgenic Mouse Facility, Duke Cancer Institute, Durham, NC, USA., von Furstenberg RJ; Division of Gastroenterology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA., Stripp BR; Department of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Agarwal P; Division of Surgical Sciences, Department of Surgery, Duke University School of Medicine, Durham, NC, USA., Borowsky AD; Department of Pathology and Laboratory Medicine and The Center for Comparative Medicine, University of California-Davis, Davis, CA, USA., Cardiff RD; Department of Pathology and Laboratory Medicine and The Center for Comparative Medicine, University of California-Davis, Davis, CA, USA., Barak LS; Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA., Caron MG; Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA., Lyerly HK; Division of Surgical Sciences, Department of Surgery, Duke University School of Medicine, Durham, NC, USA.; Department of Pathology, Duke University School of Medicine, Durham, NC, USA.; Department of Immunology, Duke University School of Medicine, Durham, NC, USA., Snyder JC; Division of Surgical Sciences, Department of Surgery, Duke University School of Medicine, Durham, NC, USA. joshua.snyder@duke.edu.; Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA. joshua.snyder@duke.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2019 Dec 02; Vol. 10 (1), pp. 5490. Date of Electronic Publication: 2019 Dec 02.
DOI: 10.1038/s41467-019-13330-y
Abstrakt: 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.
Databáze: MEDLINE