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

In a mouse model of tumours initiated by Wnt signalling in which a proportion of tumours are biclonal, that is, composed of basal and luminal clones with distinct genetic alterations, these clones are shown to cooperate to maintain tumour growth in a Wnt-dependent manner. Subclone collusion maintains Wnt-initiated cancer Tumours often display a complex subclonal organization. In a mouse model of breast cancer initiated by Wnt signalling, Allison Cleary et al . show that some tumours are biclonal — composed of basal and luminal clones with distinct genetic alterations. These clones cooperate to maintain tumour growth that is dependent on secretion of Wnt by the luminal cells. When Wnt production is blocked, basal cells carrying Hras mutations recruit other Wnt-producing cells to restore tumour growth, or one of the original clones may acquire alternative means of activating the pathway. These findings illuminate how complex cellular interactions in heterogeneous tumours might sway treatment outcomes. Cancer genome sequencing studies indicate that a single breast cancer typically harbours multiple genetically distinct subclones 1 , 2 , 3 , 4 . 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 5 , 6 . 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 7 , 8 , 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 Wnt1 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 9 . 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 Hras wild-type subclones. Both subclones are required for efficient tumour propagation, which strictly depends on luminally produced Wnt1. When biclonal tumours were challen