Interleukin-6 trans-signaling is a candidate mechanism to drive progression of human DCCs during clinical latency

Melanie Werner-Klein (), Ana Grujovic, Christoph Irlbeck, Milan Obradović, Martin Hoffmann, Huiqin Koerkel-Qu, Xin Lu, Steffi Treitschke, Cäcilia Köstler, Catherine Botteron, Kathrin Weidele, Christian Werno, Bernhard Polzer, Stefan Kirsch, Miodrag Gužvić, Jens Warfsmann, Kamran Honarnejad, Zbigniew Czyz, Giancarlo Feliciello, Isabell Blochberger, Sandra Grunewald, Elisabeth Schneider, Gundula Haunschild, Nina Patwary, Severin Guetter, Sandra Huber, Brigitte Rack, Nadia Harbeck, Stefan Buchholz, Petra Rümmele, Norbert Heine, Stefan Rose-John and Christoph A. Klein ()
Additional contact information
Melanie Werner-Klein: University of Regensburg
Ana Grujovic: University of Regensburg
Christoph Irlbeck: University of Regensburg
Milan Obradović: University of Regensburg
Martin Hoffmann: Fraunhofer Institute for Toxicology and Experimental Medicine
Huiqin Koerkel-Qu: University of Regensburg
Xin Lu: Fraunhofer Institute for Toxicology and Experimental Medicine
Steffi Treitschke: Fraunhofer Institute for Toxicology and Experimental Medicine
Cäcilia Köstler: Fraunhofer Institute for Toxicology and Experimental Medicine
Catherine Botteron: Fraunhofer Institute for Toxicology and Experimental Medicine
Kathrin Weidele: Fraunhofer Institute for Toxicology and Experimental Medicine
Christian Werno: Fraunhofer Institute for Toxicology and Experimental Medicine
Bernhard Polzer: Fraunhofer Institute for Toxicology and Experimental Medicine
Stefan Kirsch: Fraunhofer Institute for Toxicology and Experimental Medicine
Miodrag Gužvić: University of Regensburg
Jens Warfsmann: Fraunhofer Institute for Toxicology and Experimental Medicine
Kamran Honarnejad: Fraunhofer Institute for Toxicology and Experimental Medicine
Zbigniew Czyz: University of Regensburg
Giancarlo Feliciello: Fraunhofer Institute for Toxicology and Experimental Medicine
Isabell Blochberger: University of Regensburg
Sandra Grunewald: University of Regensburg
Elisabeth Schneider: University of Regensburg
Gundula Haunschild: University of Regensburg
Nina Patwary: University of Regensburg
Severin Guetter: University of Regensburg
Sandra Huber: University of Regensburg
Brigitte Rack: LMU University Hospital
Nadia Harbeck: LMU University Hospital
Stefan Buchholz: University Medical Center Regensburg
Petra Rümmele: University of Regensburg
Norbert Heine: University of Regensburg
Stefan Rose-John: Christian-Albrechts-Universität Kiel
Christoph A. Klein: University of Regensburg

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18701-4

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