Abstract
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.
Highlights
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
We identified interleukin-6 (IL-6) transsignaling as a pathway that (i) activates normal and premalignant cells, (ii) induces a proliferative stem/progenitor-like phenotype in mammary epithelial cells, and (iii) whose activation in disseminated cancer cells (DCCs) depends on regulatory niche cells in bone marrow (BM)
01234567 −Log[10] adjusted p value and transcriptome analysis and isolated genomic DNA and mRNA from the same single cell[5,14]. This approach fails in 10–50%13,14,28 and a copy number alteration (CNA) profile cannot be obtained for every cell, we found that 50% and 88% of successfully analyzed EpCAM+ cells from M0- and M1-stage patients, respectively, harbored CNAs (Fig. 3a and Supplementary Fig. 1a, b)
Summary
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. Its manifestation may take considerable time[1,3,7] Such data are consistent with the observation that early disseminated cancer cells (DCCs) often lack critical genetic and genomic alterations, which they need to acquire at the distant site in breast and other cancers. We identified interleukin-6 (IL-6) transsignaling as a pathway that (i) activates normal and premalignant cells, (ii) induces a proliferative stem/progenitor-like phenotype in mammary epithelial cells, and (iii) whose activation in DCCs depends on regulatory niche cells in BM These data shed light onto the so far dark stage of early metastasis formation in patients. It may inform about future ways to delay or prevent metachronous metastasis in patients whose breast cancer is diagnosed to be locally confined by standard clinical means
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