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

: Werner-Klein, M.; Grujovic, A.; Irlbeck, C.; Obradović, M.; Hoffmann, M.; Koerkel-Qu, H.; Lu, X.; Treitschke, S.; Köstler, C.; Botteron, C.; Weidele, K.; Werno, C.; Polzer, B.; Kirsch, S.; Gužvić, M.; Warfsmann, J.; Honarnejad, K.; Czyz, Z.; Feliciello, G.; Blochberger, I.; Grunewald, S.; Schneider, E.; Haunschild, G.; Patwary, N.; Guetter, S.; Huber, S.; Rack, B.; Harbeck, N.; Buchholz, S.; Rümmele, P.; Heine, N.; Rose-John, S.; Klein, C.A.

Volltext ()

Nature Communications 11 (2020), Nr.1, Art. 4977
ISSN: 2041-1723
Deutsche Forschungsgemeinschaft DFG
KL 1233/10-2
Zeitschriftenaufsatz, Elektronische Publikation
Fraunhofer ITEM ()

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.