biostudies-literatureYum MKCancer Research UKEuropean Research CouncilMedical Research CouncilWellcome Trust442-447https://www.ebi.ac.uk/biostudies/studies/S-EPMC7614896biostudies-literatureUnknown594(7863)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^loCD81⁺ 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.NatureTracing oncogene-driven remodelling of the intestinal stem cell niche.PMC7614896639050107633/Z/15/Z098357/Z/12/Z219478/Z/19/Z09209623363MC_PC_1723067941125636Dabrowska CFink JEngland FKim JKHan SAzzarelli RYum MKLee ETrendafilova TKoo BKPshenichnaya IPhilpott AStange DEChatzeli LSimons BDWu SSMustata RLee JHfalseTracing oncogene-driven remodelling of the intestinal stem cell niche.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^loCD81⁺ 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.2021-01-01T00:00:00Z2021 Jun2025-04-04T02:26:06.717Z2025-04-04T02:26:06.717ZS-EPMC76148963407912610.1038/s41586-021-03605-0