Cross-talk with lung epithelial cells regulates Sfrp2-mediated latency in breast cancer dissemination

The process of metastasis is complex(1). In breast cancer, there are frequently long timespans between cells leaving the primary tumour and growth of overt metastases (2,3). Reasons for disease indolence and subsequent transitioning back to aggressive growth include interplay with myeloid and fibroblastic cells in the tumour microenvironment and ongoing immune surveillance (4–6). However, the signals causing actively growing cells to enter into an indolent state, and enabling them to survive for extended periods of time, are not well understood. We reveal how the behaviour of indolent breast cancer cells in the lung is determined by their interactions with alveolar epithelial cells, in particular AT1 cells. This promotes the formation of fibronectin (FN) fibrils by indolent cells that drive integrin-dependent pro-survival signals. Combined in vivo RNA sequencing and drop-out screening identified Secreted frizzled-related protein 2 (Sfrp2) as a key mediator of this interaction. Sfrp2 is induced in breast cancer cells by signals emanating from lung epithelial cells and promotes FN fibril formation and survival, while blockade of Sfrp2 expression reduces the burden of indolent disease.