Werner-Klein, M.M.Werner-KleinGrujovic, A.A.GrujovicIrlbeck, C.C.IrlbeckObradovic, M.M.ObradovicHoffmann, M.M.HoffmannKoerkel-Qu, H.H.Koerkel-QuLu, X.X.LuTreitschke, S.S.TreitschkeKöstler, C.C.KöstlerBotteron, C.C.BotteronWeidele, K.K.WeideleWerno, C.C.WernoPolzer, B.B.PolzerKirsch, S.S.KirschGuzvic, M.M.GuzvicWarfsmann, J.J.WarfsmannHonarnejad, K.K.HonarnejadCzyz, Z.Z.CzyzFeliciello, G.G.FelicielloBlochberger, I.I.BlochbergerGrunewald, S.S.GrunewaldSchneider, E.E.SchneiderHaunschild, G.G.HaunschildPatwary, N.N.PatwaryGuetter, S.S.GuetterHuber, S.S.HuberRack, B.B.RackHarbeck, N.N.HarbeckBuchholz, S.S.BuchholzRümmele, P.P.RümmeleHeine, N.N.HeineRose-John, S.S.Rose-JohnKlein, C.A.C.A.Klein2022-03-062022-03-062020https://publica.fraunhofer.de/handle/publica/26522210.1038/s41467-020-18701-4Although 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.en610620journal article