TY - JOUR TI - Interleukin-6 trans-signaling is a candidate mechanism to drive progression of human DCCs during clinical latency AU - Werner-Klein, Melanie AU - Grujovic, Ana AU - Irlbeck, Christoph AU - Obradović, Milan AU - Hoffmann, Martin AU - Koerkel-Qu, Huiqin AU - Lu, Xin AU - Treitschke, Steffi AU - Köstler, Cäcilia AU - Botteron, Catherine AU - Weidele, Kathrin AU - Werno, Christian AU - Polzer, Bernhard AU - Kirsch, Stefan AU - Gužvić, Miodrag AU - Warfsmann, Jens AU - Honarnejad, Kamran AU - Czyz, Zbigniew AU - Feliciello, Giancarlo AU - Blochberger, Isabell AU - Grunewald, Sandra AU - Schneider, Elisabeth AU - Haunschild, Gundula AU - Patwary, Nina AU - Guetter, Severin AU - Huber, Sandra AU - Rack, Brigitte AU - Harbeck, Nadia AU - Buchholz, Stefan AU - Rümmele, Petra AU - Heine, Norbert AU - Rose-John, Stefan AU - Klein, Christoph A. T2 - Nature Communications AB - 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 profile rare bone marrow-derived disseminated cancer cells (DCCs) long before manifestation of metastasis and identify IL6/PI3K-signaling as candidate pathway for DCC activation. Surprisingly, and similar to mammary epithelial cells, DCCs lack membranous IL6 receptor expression and mechanistic dissection reveals IL6 trans-signaling to regulate a stem-like state of mammary epithelial cells via gp130. Responsiveness to IL6 trans-signals is found to be niche-dependent as bone marrow stromal and endosteal cells down-regulate gp130 in premalignant mammary epithelial cells as opposed to vascular niche cells. PIK3CA activation renders cells independent from IL6 trans-signaling. Consistent with a bottleneck function of microenvironmental DCC control, we find 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. DA - 2020/10/05/ PY - 2020 DO - 10.1038/s41467-020-18701-4 DP - www.nature.com VL - 11 IS - 1 SP - 4977 LA - en SN - 2041-1723 UR - https://www.nature.com/articles/s41467-020-18701-4 Y2 - 2020/10/05/20:51:21 ER -