Interleukin-6 trans-signaling is a candidate mechanism to drive progression of human DCCs during periods of clinical latency

Although thousands of breast cancer cells disseminate and home to bone marrow until primary surgery, usually less than a handful will succeed in establishing manifest metastases months to years later. To identify signals that support survival or outgrowth in patients, we profiled rare bone marrow-derived disseminated cancer cells (DCCs) long before manifestation of metastasis and identified IL6/PI3K-signaling as candidate pathway for DCC activation. Surprisingly, and similar to mammary epithelial cells, DCCs lacked membranous IL6 receptor expression and mechanistic dissection revealed IL6 trans-signaling to regulate a stem-like state of mammary epithelial cells via gp130. Responsiveness to IL6 trans-signals was found to be niche-dependent as bone marrow stromal and endosteal cells down-regulated gp130 in premalignant mammary epithelial cells as opposed to vascular niche cells. PIK3CA activation rendered cells independent from IL6 trans-signaling. Consistent with a bottleneck function of microenvironmental DCC control, we found PIK3CA mutations highly associated with late-stage metastatic cells while being extremely rare in early DCCs. Our data suggest that the initial steps of metastasis formation are often not cancer cell-autonomous, but also depend on microenvironmental signals.