Hebach, N. R.; Olshausen, N.; Schlag, J.; Mayer, C. D.; Henkenjohann, J.; Kraft, T.; Bang, S.; Thommek, C.; Nürnberg, C.; Horsak, N. E.; Hoffmann, D. C.; Kourtesakis, A.; Porzberg, N.; Flores Valle, A.; Linke, C. Z.; Yang, Y.; Azorin, D. D.; Hausmann, D.; Venkataramani, V.; Meier, F.; Ratliff, M.; Seifert, M.; Westphal, D.; Breckwoldt, M. O.; Timmer, J.; Johnsson, K.; Wick, W.; Winkler, F.; Karreman, M. A.

Communication in multicellular networks is a cancer-intrinsic neural feature and crucial for primary brain tumor growth and resistance, but it is unclear whether brain metastases (BrM), the most common and deadliest brain malignancy, are also driven by communicating cancer networks. Using intravital two-photon microscopy in awake mice, clinical specimens, and Ca2+ integrators, we demonstrate that brain-colonizing breast and lung cancer and melanoma cells display gap-junction-dependent, coordinated Ca2+ activity in multicellular, cancer-cell intrinsic networks, which drives their proliferation. Mechanistically, Ca2+ oscillations induce transcription of immediate early genes, adoption of a neuronal expression profile, and cell cycle progression. While many of those features are enriched in BrM, all investigated cancer cell lines showed collective Ca2+ activity. Therapeutically, blocking Ca2+ activity with gap junction inhibitors reduces BrM burden in mouse models. Here we show communicating cancer cell syncytia as drivers of BrM growth, pointing to a targetable pathomechanism, and potentially a new pan-cancer hallmark.