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.

中文翻译：

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白细胞介素6反信号是在临床潜伏期驱动人类DCC进展的候选机制

尽管成千上万的乳腺癌细胞会散布并归巢于骨髓，直到进行初次手术，但通常只有不到一小部分会在数月至数年后成功建立明显的转移灶。为了确定支持患者生存或增长的信号，我们在转移灶出现之前很久就对稀有的骨髓源性弥散性癌细胞（DCC）进行了分析，并将IL6 / PI3K信号转导为DCC激活的候选途径。令人惊讶的是，与乳腺上皮细胞相似，DCC缺乏膜性IL6受体表达，并且机械解剖显示IL6反信号可通过gp130调节乳腺上皮细胞的干样状态。发现IL6跨信号的反应是利基依赖性的，因为在恶性前乳腺上皮细胞中，骨髓基质和骨内膜细胞下调了gp130，而不是血管利基细胞。PIK3CA激活使细胞独立于IL6反信号转导。与微环境DCC控制的瓶颈功能一致，我们发现PIK3CA突变与晚期转移细胞高度相关，而在早期DCC中极为罕见。我们的数据表明，转移形成的初始步骤通常不是癌细胞自主的，而是取决于微环境信号。我们发现PIK3CA突变与晚期转移细胞高度相关，而在早期DCC中极为罕见。我们的数据表明，转移形成的初始步骤通常不是癌细胞自主的，而是取决于微环境信号。我们发现PIK3CA突变与晚期转移细胞高度相关，而在早期DCC中极为罕见。我们的数据表明，转移形成的初始步骤通常不是癌细胞自主的，而是取决于微环境信号。