Barcoding reveals complex clonal dynamics of de novo transformed human mammary cells

Most human breast cancers have already diversified genomically when they first become clinically evident, by which time extensive heterogeneous histopathologies, transcriptomes and growth patterns are also apparent. Accordingly, important initial events and the cellular context in which they occur have been difficult to characterize. Using DNA barcoding, we now demonstrate the high efficiency with which both purified basal and luminal cells isolated directly from normal adult human mammary tissue can be rapidly transformed by a single oncogene (KRASG12D) resulting in the production within 8 weeks in vivo of serially transplantable, polyclonal, invasive ductal carcinomas that are phenotypically heterogeneous and transcriptionally distinct from the initial cells transduced. Barcoding also revealed a consistent dramatic change in the clonal content of passaged tumours. This system thus provides a powerful new platform for examining early events in the genesis, evolution and treatment response of malignant human mammary cells generated using defined mutations.EGA study EGAS00001001310

大多数人类乳腺癌在首次临床确诊时即已发生基因组多样化，此时广泛的异质性组织病理学特征、转录组谱及生长模式均已显现。因此，其关键起始事件及发生的细胞微环境一直难以被精准表征。本研究借助DNA条形码（DNA barcoding）技术证实，直接从正常成人乳腺组织中分离得到的纯化基底细胞与腔细胞，均可通过单一致癌基因KRASG12D实现快速转化，并可在8周内于体内形成可连续移植的多克隆浸润性导管癌；此类肿瘤具有表型异质性，且转录组特征与初始转导细胞显著不同。条形码技术还揭示了传代肿瘤的克隆组成始终发生显著变化。因此，该系统为探究经明确突变构建的恶性人类乳腺细胞的发生、演进及治疗响应中的早期事件提供了全新的高效研究平台。EGA study EGAS00001001310