Werner-Klein, Melanie and Grujovic, Ana and Irlbeck, Christoph and Hoffmann, Martin and Koerkel-Qu, Huiqin and Lu, Xin and Treitschke, Steffi and Koestler, Cacilia and Botteron, Catherine and Weidele, Kathrin and Werno, Christian and Polzer, Bernhard and Kirsch, Stefan and Guzvic, Miodrag and Warfsmann, Jens and Honarnejad, Kamran and Czyz, Zbigniew and Feliciello, Giancarlo and Blochberger, Isabell and Grunewald, Sandra and Schneider, Elisabeth and Haunschild, Gundula and Patwary, Nina and Guetter, Severin and Huber, Sandra and Rack, Brigitte and Harbeck, Nadia and Buchholz, Stefan and Ruemmele, Petra and Heine, Norbert and Rose-John, Stefan and Klein, Christoph A. (2020) Interleukin-6 trans-signaling is a candidate mechanism to drive progression of human DCCs during clinical latency. NATURE COMMUNICATIONS, 11 (1): 4977. ISSN 2041-1723,
Full text not available from this repository. (Request a copy)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. Metastatic dissemination in breast cancer patients occurs early in malignant transformation, raising questions about how disseminated cancer cells (DCC) progress at distant sites. Here, the authors show that DCCs in bone marrow are activated via IL6-trans-signaling and thereby acquire stemness traits relevant for metastasis formation.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | DISSEMINATED TUMOR-CELLS; COMPARATIVE GENOMIC HYBRIDIZATION; METASTATIC BREAST-CANCER; BONE-MARROW; IN-VIVO; EARLY DISSEMINATION; SOLUBLE GP130; STEM-CELLS; RECEPTOR; IL-6; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Frauenheilkunde und Geburtshilfe (Schwerpunkt Frauenheilkunde) Medicine > Lehrstuhl für Pathologie Medicine > Zentren des Universitätsklinikums Regensburg > Zentrum für Plastische-, Hand- und Wiederherstellungschirurgie Medicine > Lehrstuhl für experimentelle Medizin und Therapieverfahren |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 12 Mar 2021 07:53 |
| Last Modified: | 12 Mar 2021 07:53 |
| URI: | https://pred.uni-regensburg.de/id/eprint/43602 |
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