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Tracing oncogene-driven remodelling of the intestinal stem cell niche

Title
Tracing oncogene-driven remodelling of the intestinal stem cell niche
Authors
Yum, Min KyuHan, SeungminFink, JuergenWu, Szu-Hsien SamDabrowska, CatherineTrendafilova, TeodoraMustata, RoxanaChatzeli, LemoniaAzzarelli, RobertaPshenichnaya, IrinaLee, Eun MinEngland, FrancesKim, Jong KyoungStange, Daniel E.Philpott, AnnaLee, Joo-HyeonKoo, Bon-KyoungSimons, Benjamin D.
DGIST Authors
Yum, Min Kyu; Han, Seungmin; Fink, Juergen; Wu, Szu-Hsien Sam; Dabrowska, Catherine; Trendafilova, Teodora; Mustata, Roxana; Chatzeli, Lemonia; Azzarelli, Roberta; Pshenichnaya, Irina; Lee, Eun Min; England, Frances; Kim, Jong Kyoung; Stange, Daniel E.; Philpott, Anna; Lee, Joo-Hyeon; Koo, Bon-Kyoung; Simons, Benjamin D.
Issue Date
2021-06
Citation
Nature, 594(7863), 442
Type
Article
Keywords
MICROENVIRONMENTAL REGULATIONFIELD CANCERIZATIONTUMOR PROGRESSIONHOMEOSTASISCOMPETITIONCANCERDIFFERENTIATIONEPITHELIUMDYNAMICSSIGNALS
ISSN
0028-0836
Abstract
Interactions between tumour cells and the surrounding microenvironment contribute to tumour progression, metastasis and recurrence(1-3). Although mosaic analyses in Drosophila have advanced our understanding of such interactions(4,5), 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 PDGFR(lo)CD81(+) 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.
URI
http://hdl.handle.net/20.500.11750/15421
DOI
10.1038/s41586-021-03605-0
Publisher
Nature Publishing Group
Files:
There are no files associated with this item.
Collection:
Department of New BiologyETC1. Journal Articles
Department of New BiologyLaboratory of Single-Cell Genomics1. Journal Articles


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