Abstract: Brain metastasis (BM) is a severe and devastating complication of advanced malignant melanoma, lung cancer and breast cancer. The limited response of brain metastasis to established therapies underscores both the need to find novel therapies. We use intravital microscopy in preclinical mouse models, in vitro live cell imaging, electron microcopy and correlative microscopy to better understand the underlying mechanisms of BM formation and the interaction with the tumor microenvironment.

We demonstrate for the first time that melanoma brain metastases (MBrM) exhibit spontaneous calcium oscillations. We elucidated the molecular mechanism behind these oscillations and showed that they not only depend on an interplay of calcium-induced calcium release pathways and store-operated calcium entry, but also gap-junction mediated crosstalk between tumour cells. Intercellular contacts were confirmed by dye transfer experiments. Importantly, inhibition of gap junctions significantly reduced calcium oscillations in vitro, as well as tumor proliferation both in vitro and in vivo. Our future focus is on uncovering the downstream pathways activated by these calcium oscillations.

Moreover, we discovered functional glutamatergic synapses between neurons and BrM, which can also induce calcium transients. In melanoma and breast cancer BrM, pharmacological and genetic inhibition of these synapses leads to a reduction of brain metastatic growth. These findings underscore the roles of network communication and neuron-tumor crosstalk in BrM pathobiology, revealing potential new therapeutic targets to combat this disease.

Host: Paul Verkade