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While thousands of breast cancer cells disseminate and home to bone marrow (BM) until primary surgery, usually less than a handful will succeed in establishing manifest metastases months to years later. Signals and mechanisms determining failure or success of disseminated cancer cells (DCCs) are largely unknown and there is no in vivo model available to study the spontaneous progression and genomic evolution from early bone marrow infiltration to manifestation of bone metastasis, as spontaneous or transgenic mouse models do not generate bone metastases. We therefore profiled DCCs from BM of breast cancer patients long before manifestation of metastasis by RNAseq to identify signals supporting survival or outgrowth of DCCs and identified IL6/PTEN/PI3K signaling as candidate pathway for DCC activation. Since early DCCs often display close-to-normal genomes we used mammary epithelial cells ex vivo isolated from reduction mammoplasties and immortalized pre-malignant breast cancer cell lines as model for functional testing in vitro. Using specific activators and inhibitors of IL6 signaling revealed that IL6 trans, but not classical signaling, regulates stemness of mammary epithelial cells. Moreover, knock-down of PTEN revealed that PI3K/PTEN pathway activation renders cells independent of IL6 trans-signaling. Interestingly, gp130 expression, a pre-requisite for IL6 trans-signaling was found to be down-regulated by bone marrow stromal and endosteal, but not vascular niche cells, and as a consequence the number of cells with stem-like ability was significantly reduced. Consistent with a bottleneck function of microenvironmental DCC control, we found PIK3CA mutations highly associated with late-stage metastatic DCCs and CTCs while generally absent in early DCCs. Our data suggest that the initial steps of metastasis formation depend on microenvironmental signals and are not cancer cell-autonomous. Citation Format: Melanie Werner-Klein, Ana Grujovic, Milan Obradovic, Martin Hoffmann, Xin Lu, Stefan Kirsch, Steffi Treitschke, Cäcilia Köstler, Kathrin Weidele, Christoph Irlbeck, Catherine Botteron, Christian Werno, Bernhard Polzer, Miodrag Guzvic, Stefan Buchholz, Petra Rümmele, Norbert Heine, Stefan Rose-John, Christoph A. Klein. Interleukin 6 transsignaling is a candidate mechanism to drive progression of human DCCs during periods of clinical latency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-312.