Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer

Nature. 2016 May 26;533(7604):493-498. doi: 10.1038/nature18268. Epub 2016 May 18.

Abstract

Brain metastasis represents a substantial source of morbidity and mortality in various cancers, and is characterized by high resistance to chemotherapy. Here we define the role of the most abundant cell type in the brain, the astrocyte, in promoting brain metastasis. We show that human and mouse breast and lung cancer cells express protocadherin 7 (PCDH7), which promotes the assembly of carcinoma-astrocyte gap junctions composed of connexin 43 (Cx43). Once engaged with the astrocyte gap-junctional network, brain metastatic cancer cells use these channels to transfer the second messenger cGAMP to astrocytes, activating the STING pathway and production of inflammatory cytokines such as interferon-α (IFNα) and tumour necrosis factor (TNF). As paracrine signals, these factors activate the STAT1 and NF-κB pathways in brain metastatic cells, thereby supporting tumour growth and chemoresistance. The orally bioavailable modulators of gap junctions meclofenamate and tonabersat break this paracrine loop, and we provide proof-of-principle that these drugs could be used to treat established brain metastasis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Astrocytes / cytology
  • Astrocytes / drug effects
  • Astrocytes / metabolism*
  • Benzamides / pharmacology
  • Benzamides / therapeutic use
  • Benzopyrans / pharmacology
  • Benzopyrans / therapeutic use
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology*
  • Brain Neoplasms / secondary*
  • Breast Neoplasms / pathology
  • Cadherins / metabolism
  • Cell Line, Tumor
  • Coculture Techniques
  • Connexin 43 / metabolism
  • Drug Resistance, Neoplasm
  • Female
  • Gap Junctions / drug effects
  • Gap Junctions / metabolism*
  • Humans
  • Immunity, Innate
  • Interferon-alpha / metabolism
  • Lung Neoplasms / pathology
  • Meclofenamic Acid / pharmacology
  • Meclofenamic Acid / therapeutic use
  • Membrane Proteins / metabolism
  • Mice
  • NF-kappa B / metabolism
  • Nucleotides, Cyclic / metabolism*
  • Paracrine Communication / drug effects
  • STAT1 Transcription Factor / metabolism
  • Tumor Necrosis Factors / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Benzamides
  • Benzopyrans
  • Cadherins
  • Connexin 43
  • Interferon-alpha
  • MPYS protein, mouse
  • Membrane Proteins
  • NF-kappa B
  • Nucleotides, Cyclic
  • PCDH7 protein, human
  • PCDH7 protein, mouse
  • STAT1 Transcription Factor
  • STING protein, human
  • Tumor Necrosis Factors
  • cyclic guanosine monophosphate-adenosine monophosphate
  • tonabersat
  • Meclofenamic Acid