Interactions between tumour cells and the surrounding microenvironment contribute to tumour progression, metastasis and recurrence^1,2,3. 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.

肿瘤细胞与周围微环境之间的相互作用有助于肿瘤进展、转移和复发^1,2,3。尽管果蝇中的镶嵌分析增进了我们对这种相互作用的理解^4,5，但在脊椎动物中设计并行方法却很困难。在这里，我们提出了一种与癌基因相关的多色报告小鼠模型——Red2Onco系统——它可以对同一组织中的突变型和野生型细胞进行差异追踪。通过将该系统应用于小肠，我们发现表达癌基因的突变隐窝改变了邻近野生型隐窝的细胞组织，从而加速了克隆漂移。表达致癌 KRAS 或 PI3K 的隐窝会分泌抑制局部干细胞活性的 BMP 配体，而具有致癌 PI3K 的隐窝诱导的PDGFR ^lo CD81 ^{+基质细胞的变化会改变 WNT 信号传导环境。}总之，这些结果表明癌基因驱动的旁分泌重塑如何创造一个不利于野生型组织维持的利基环境，促进由致癌克隆主导的领域转化。