Tumour cell heterogeneity maintained by cooperating subclones in Wnt-driven mammary cancers

摘要

Cancer genome sequencing studies indicate that a single breast cancer typically harbours multiple genetically distinct subclones. As carcinogenesis involves a breakdown in the cell-cell cooperation that normally maintains epithelial tissue architecture, individual subclones within a malignant microenvironment are commonly depicted as self-interested competitors. Alternatively, breast cancer subclones might interact cooperatively to gain a selective growth advantage in some cases. Although interclonal cooperation has been shown to drive tumorigenesis in fruitfly models, definitive evidence for functional cooperation between epithelial tumour cell subclones in mammals is lacking. Here we use mouse models of breast cancer to show that interclonal cooperation can be essential for tumour maintenance. Aberrant expression of the secreted signalling molecule Wntl generates mixed-lineage mammary tumours composed of basal and luminal tumour cell subtypes, which purportedly derive from a bipotent malignant progenitor cell residing atop a tumour cell hierarchy. Using somatic Hras mutations as clonal markers, we show that some Wnt tumours indeed conform to a hierarchical configuration, but that others unexpectedly harbour genetically distinct basal Hras mutant and luminal ifras wild-type subclones. Both subclones are required for efficient tumour propagation, which strictly depends on lumin-ally produced Wntl. When biclonal tumours were challenged with Wnt withdrawal to simulate targeted therapy, analysis of tumour regression and relapse revealed that basal subclones recruit heterologous Wnt-producing cells to restore tumour growth. Alternatively, in the absence of a substitute Wnt source, the original subclones often evolve to rescue Wnt pathway activation and drive relapse, either by restoring cooperation or by switching to a defector strategy. Uncovering similar modes of interclonal cooperation in human cancers may inform efforts aimed at eradicating tumour cell communities.%本期封面所示为来自表达一个世系标记(绿色）的供体小鼠(红色)的基底乳腺肿瘤细胞与来自主体的上皮细胞相互混杂。左边伸长的乳腺导管在没有被来自供体的肿瘤亚克隆滲透的情况下保留了正常的双层架构。肿瘤经常表现出复杂的亚克隆组织。在由Wnt信号作用引发的乳腺癌的一个小鼠模型中，Allison Cleary等人发现，有些肿瘤是双克隆的，即由具有截然不同基因改变的基底克隆和管腔克隆组成。这些克隆相互合作来维持肿瘤生长，后者取决于管腔细胞对Wnt的分泌。当Wnt的生成被阻断时，携带Hras突变的基底细胞会招募其他能生成Wnt的细胞来恢复肿瘤生长，否则原始克隆当中的一个可能会获得激活该通道的其他手段。这些发现揭示了异质肿瘤内的复杂细胞相互作用会怎样改变治疗结果。