Carcinoma–astrocyte gap junctions promote brain metastasis by cGAMP transfer

Abstract

SUMMARY 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. Breast and lung cancer cells express protocadherin 7 (PCDH7) to favor the assembly of carcinoma-astrocyte gap junctions composed of connexin 43 (Cx43). Once engaged with the astrocyte gap-junctional network, brain metastatic cancer cells employ these channels to transfer the second messenger cGAMP to astrocytes, activating the STING pathway and production of inflammatory cytokines IFNα and TNFα. As paracrine signals, these factors activate the STAT1 and NF-κB pathways in brain metastatic cells, which support tumour growth and chemoresistance. The orally bioavailable modulators of gap junctions meclofenamate and tonabersat break this paracrine loop, and we provide proof-of-principle for the applicability of this therapeutic strategy to treat established brain metastasis.

Innate immune signaling and regulation in cancer immunotherapy

“…In this model, activation of STING by DNA or STING agonists promoted tolerogenic responses by induction of indoleamine 2,3 dioxygenase (IDO), which activated Tregs to promote dominant inhibitory T cell regulation [65,66]. A recent study has linked the activation of STING and production of inflammatory cytokines to brain metastasis and chemoresistance [63]. In this case, brain metastatic cancer cells established gap junctions with astrocytes and used these channels to transfer cGAMP.…”

“…Together, these data are consistent with the idea that STING activation in host APCs in the tumor is triggered upon successful transfer of DNA from tumor cells. However, there is also the potential to transfer cGAMP directly, which in some model systems has been reported to occur through gap junctions [62,63]. The detailed cell biology of STING pathway activation in the cancer context is the subject of current investigation.…”

Orchestration of the crosstalk between astrocytes and cancer cells affects the treatment and prognosis of lung cancer sufferers with brain metastasis

“…Chen et al showed that it result from the establishment of gap junctions between cancer cells and reactive astrocytes (27). Researchers observed that cancer cells and astrocytes communicate with each other through gap junctions, and the communication activates pro-survival signals consistently.…”

“…It is shown that by means of protocadherin 7 (PCDH7), metastatic cells selectively form connexin 43 (Cx43) gap junctions with astrocytes, then cyclic GMP-AMP (cGAMP) is allowed to pass from cancer cells to astrocytes to activate STING, an inherent immune response pathway to cytosolic double-stranded DNA (dsDNA). The resulting production of tumour necrosis factor (TNF) and interferon-α (IFNα) in astrocytes supports outgrowth and drug-resistance in metastatic cells (27).…”

Closing the gap: astrocytes and brain metastasis

“…In a recent issue of Nature, Chen et al [1] build upon this work to describe novel mechanisms set in motion when tumors expand in the brain parenchyma. Astrocytes play a key role in this process ( Figure 1).…”