Carcinoma–astrocyte gap junctions drive growth and chemoresistance of brain metastases.
Major finding: Carcinoma–astrocyte gap junctions drive growth and chemoresistance of brain metastases.
Mechanism: PCDH7-induced gap junctions drive cGAMP transfer to trigger the cGAS–STING response in astrocytes.
Impact: Modulation of gap junctions may be a potential therapeutic strategy to target brain metastases.
Astrocytes in the normal brain parenchyma exhibit a protective role against brain metastatic cells, but it is not clear how astrocytes may induce the formation of brain metastases. Chen, Boire, and colleagues investigated the role of astrocytic gap junctions in promoting breast and lung cancer brain metastasis, and showed that expression of the critical astrocytic gap junction protein connexin 43 (CX43, encoded by GJA1) was elevated in astrocytes compared to brain metastases and in brain metastases compared to primary tumors or matched normal tissues. Expression of the integral membrane protein protocadherin 7 (PCDH7), which mediates cell–cell adhesion and has been shown to be upregulated in breast and lung cancer brain metastases, was increased in brain metastases compared to components of normal brain parenchyma, including astrocytes and microglia. Depletion of GJA1 or PCDH7 in brain metastatic cells resulted in reduced dye transfer from cancer cells to astrocytes in vitro and decreased growth of brain metastases in murine models of breast and lung cancers in vivo. Mechanistically, cancer cells formed cell–cell adhesions with astrocytes via PCDH7 to induce the formation of cancer cell–astrocyte CX43 gap junctions, which enabled the transfer of cyclic GMP–AMP (cGAMP) from cancer cells to normal astrocytes and the astrocytic activation of the cyclic GMPAMP (cGAS)–stimulator of interferon genes (STING) pathway. Activation of cGAS–STING, which drives the innate immune response to cytosolic DNA, resulted in the astrocytic production of IFNα and TNF and the activation of STAT1 and NF-κB signaling in brain metastatic cells. Treatment with gap junction inhibitors decreased brain metastases in murine breast cancer models, and depletion of GJA1 or PCDH7 in established brain metastases enhanced chemosensitivity. Together, these results show that the formation of cancer cell–astrocyte gap junctions promotes brain metastasis growth, and inhibition of gap junctions may be a potential therapy to treat and enhance chemosensitivity of brain metastases.