Synaptic proximity enables NMDAR signalling to promote brain metastasis

Qiqun Zeng, Iacovos P. Michael, Peng Zhang, Sadegh Saghafinia, Graham Knott, Wei Jiao, Brian D. McCabe, José A. Galván, Hugh P. C. Robinson, Inti Zlobec, Giovanni Ciriello and Douglas Hanahan ()
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Qiqun Zeng: Swiss Federal Institute of Technology Lausanne (EPFL)
Iacovos P. Michael: Swiss Federal Institute of Technology Lausanne (EPFL)
Peng Zhang: Children’s National Medical Center
Sadegh Saghafinia: Swiss Federal Institute of Technology Lausanne (EPFL)
Graham Knott: Swiss Federal Institute of Technology Lausanne (EPFL)
Wei Jiao: Swiss Federal Institute of Technology Lausanne (EPFL)
Brian D. McCabe: Swiss Federal Institute of Technology Lausanne (EPFL)
José A. Galván: University of Bern
Hugh P. C. Robinson: University of Cambridge
Inti Zlobec: University of Bern
Giovanni Ciriello: Swiss Cancer Center Leman (SCCL)
Douglas Hanahan: Swiss Federal Institute of Technology Lausanne (EPFL)

Nature, 2019, vol. 573, issue 7775, 526-531

Abstract: Abstract Metastasis—the disseminated growth of tumours in distant organs—underlies cancer mortality. Breast-to-brain metastasis (B2BM) is a common and disruptive form of cancer and is prevalent in the aggressive basal-like subtype, but is also found at varying frequencies in all cancer subtypes. Previous studies revealed parameters of breast cancer metastasis to the brain, but its preference for this site remains an enigma. Here we show that B2BM cells co-opt a neuronal signalling pathway that was recently implicated in invasive tumour growth, involving activation by glutamate ligands of N-methyl-d-aspartate receptors (NMDARs), which is key in model systems for metastatic colonization of the brain and is associated with poor prognosis. Whereas NMDAR activation is autocrine in some primary tumour types, human and mouse B2BM cells express receptors but secrete insufficient glutamate to induce signalling, which is instead achieved by the formation of pseudo-tripartite synapses between cancer cells and glutamatergic neurons, presenting a rationale for brain metastasis.

Date: 2019
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DOI: 10.1038/s41586-019-1576-6

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