Tracing oncogene-driven remodelling of the intestinal stem cell niche

Autor: Catherine Dabrowska, Lemonia Chatzeli, Roxana C. Mustata, Seungmin Han, Roberta Azzarelli, Daniel E. Stange, Eunmin Lee, Irina Pshenichnaya, Min Kyu Yum, Bon-Kyoung Koo, Jong Kyoung Kim, Frances J. England, Juergen Fink, Teodora Trendafilova, Anna Philpott, Szu-Hsien Sam Wu, Benjamin D. Simons, Joo-Hyeon Lee
Rok vydání: 2021
Předmět:
Zdroj: Nature. 594:442-447
ISSN: 1476-4687
0028-0836
Popis: 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. By inducing changes in surrounding tissue, mutant intestinal stem cells create an unfavourable niche environment that gives them a competitive advantage over non-mutant neighbours.
Databáze: OpenAIRE
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