Tracing oncogene-driven remodelling of the intestinal stem cell niche.
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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.
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1476-4687
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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)