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Tracing oncogene-driven remodelling of the intestinal stem cell niche.

Accepted version
Peer-reviewed

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Authors

Yum, Min Kyu 
Han, Seungmin 
Fink, Juergen 
Dabrowska, Catherine 

Abstract

Interactions between tumour cells and the surrounding microenvironment contribute to tumour progression, metastasis and recurrence1-3. Although mosaic analyses in Drosophila have advanced our understanding of such interactions4,5, it has been difficult to engineer parallel approaches in vertebrates. Here we present an oncogene-associated, multicolour reporter mouse model-the Red2Onco system-that allows differential tracing of mutant and wild-type cells in the same tissue. By applying this system to the small intestine, we show that oncogene-expressing mutant crypts alter the cellular organization of neighbouring wild-type crypts, thereby driving accelerated clonal drift. Crypts that express oncogenic KRAS or PI3K secrete BMP ligands that suppress local stem cell activity, while changes in PDGFRloCD81+ stromal cells induced by crypts with oncogenic PI3K alter the WNT signalling environment. Together, these results show how oncogene-driven paracrine remodelling creates a niche environment that is detrimental to the maintenance of wild-type tissue, promoting field transformation dominated by oncogenic clones.

Description

Keywords

Animals, Clone Cells, Colorectal Neoplasms, Female, Intestine, Small, Male, Mice, Mutation, Neoplastic Stem Cells, Oncogenes, Phosphatidylinositol 3-Kinases, Reproducibility of Results, Single-Cell Analysis, Stem Cell Niche, Tumor Microenvironment, Wnt Proteins, Wnt Signaling Pathway

Journal Title

Nature

Conference Name

Journal ISSN

0028-0836
1476-4687

Volume Title

594

Publisher

Springer Science and Business Media LLC

Rights

All rights reserved
Sponsorship
Wellcome Trust (098357/Z/12/Z)
Cancer Research UK (23363)
Royal Society (RP/R1/180165)
International Human Frontier Science Program Organization
Wellcome Trust (092096/Z/10/Z)
Cancer Research Uk (None)
European Research Council (639050)
Wellcome Trust (107633/Z/15/Z)
European Research Council (679411)
Cancer Research UK (A25636)
Medical Research Council (MC_PC_17230)
Wellcome Trust (219478/Z/19/Z)
Cancer Research UK (25636)
Royal Society