Cooperative Subclones Drive Tumor Maintenance in a Breast Cancer Model

Intratumoral heterogeneity is a common feature of many human malignancies, including breast cancer, but its relevance to tumor initiation or maintenance is unclear. To gain insight into the relationship of individual subclones within a tumor, Cleary and colleagues utilized a mouse model system in which mammary tumors are driven by Wnt1 transgene expression and are characterized by the coexistence of both low Wnt1-expressing (Wnt1^low) basal and high Wnt1-expressing (Wnt1^high) luminal lineages. A subset of Wnt1-induced tumors spontaneously acquired somatic Hras mutations restricted to the basal cell subtype, suggesting a biclonal configuration; however, both lineages were required for tumor formation in secondary recipients and depended on Wnt1 expression by luminal cells. In a related mouse model with doxycycline (DOX)-inducible Wnt1 (iWNT) expression, biclonal mammary tumors regressed upon DOX withdrawal. However, iWNT-derived Hras-mutant basal tumor cells transplanted into mice constitutively expressing Wnt1 only partially regressed upon DOX withdrawal and spontaneously relapsed. In relapsed tumors, host-derived Hras–wild-type Wnt1^high luminal cells were invariably recruited by and intermingled with donor Wnt1^lowHras-mutant basal tumor cells, suggesting that Hras-mutant Wnt1^low donor basal subclones recruited host luminal epithelial cells to serve as a source of WNT1. In the absence of a substitute WNT1 source, DOX-deprived iWNT tumors regressed but frequently relapsed weeks later as DOX-independent tumors, mimicking acquired resistance to targeted therapy. The WNT pathway was reactivated in the majority of DOX-independent tumors, either through mutations that allowed DOX-independent WNT1 transgene expression or through activating mutations in Ctnnb1, which encodes the WNT1 downstream effector β-catenin. Taken together, these studies provide evidence for interclonal cooperation during tumor progression that suggests a nonhierarchical mechanism for maintenance of tumor heterogeneity that may inform therapeutic strategies and studies of tumor evolution.

Cleary AS, Leonard TL, Gestl SA, Gunther EJ. Tumour cell heterogeneity maintained by cooperating subclones in Wnt-driven mammary cancer. Nature 2014;508:113–7.

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