Journal
NATURE
Volume 594, Issue 7863, Pages 442-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41586-021-03605-0
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Funding
- Cancer Research UK Multidisciplinary Project [C52767/A23363]
- Cancer Research UK [A25636]
- Wellcome Trust [107633/Z/15/Z, 098357/Z/12/Z, 219478/Z/19/Z, 092096]
- ERC [679411, 639050]
- Human Frontier Science Program [RGY0071/2018, LT000092/2016-L]
- Interpark Bio-Convergence Center Grant Program [IBCC-IMBA-2020-01]
- Wellcome Trust
- DOC Fellowship of the Austrian Academy of Sciences
- Herchel Smith Fund
- Basic Science Research Program [NRF-2014R1A6A3A01005675]
- Royal Society EP Abraham Research Professorship [RP\R1\180165]
- Austrian Academy of Sciences
- MRC
- CRUK [C6946/A14492]
- European Research Council (ERC) [679411, 639050] Funding Source: European Research Council (ERC)
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The study utilized a multicolour reporter mouse model, the Red2Onco system, to investigate interactions between tumour cells and the microenvironment. The research revealed that oncogene-driven paracrine remodeling leads to the destruction of wild-type tissue and promotes region transformation dominated by oncogenic clones. Mechanisms such as secretion of BMP ligands and alteration of the WNT signaling environment contribute to this process.
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.
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