Author:
Werner-Klein Melanie,Grujovic Ana,Irlbeck Christoph,Obradovic Milan,Hoffmann Martin,Koerkel-Qu Huiqin,Lu Xin,Treitschke Steffi,Köstler Cäcilia,Botteron Catherine,Weidele Kathrin,Werno Christian,Polzer Bernhard,Kirsch Stefan,Guzvic Miodrag,Warfsmann Jens,Honarnejad Kamran,Czyz Zbigniew,Blochberger Isabell,Grunewald Sandra,Schneider Elisabeth,Haunschild Gundula,Patwary Nina,Guetter Severin,Huber Sandra,Buchholz Stefan,Rümmele Petra,Heine Norbert,Rose-John Stefan,Klein Christoph A.
Abstract
AbstractAlthough 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.
Publisher
Cold Spring Harbor Laboratory