Chen et al. began by attempting to explain the surprising observation that cancer cells co-cultured with astrocytes display increased survival when treated with cytotoxic agents, despite the recognized neural-protective properties of astrocytes. They then identified a heterocellular interaction between astrocytes and brain metastatic cancer cells through the establishment of hexameric connexin hemi-channels known as gap junctions. Immunohistochemistry revealed that the major gap junction protein, connexin 43 (CX43; also known as gap junction protein α1) was present at cancer cell–astrocyte interfaces in brain metastases of patients with triple-negative breast cancer and non-small cell lung cancer. Moreover, CX43 was expressed at higher levels compared with primary tumours or normal tissues, indicating a specific increased dependency upon CX43 in brain metastases.
Searching for a cell–cell adhesion molecule that could induce astrocytic gap junction formation, in conjunction with CX43, the authors identified protocadherin 7 (PCDH7), an integral membrane protein found almost exclusively in the brain. PCDH7 was highly expressed in brain metastatic cell lines compared with their parental counterparts and matched bone or lung metastatic derivatives. Consistent with a role for both PCDH7 and CX43 in gap junction assembly, knockdown of either protein resulted in decreased dye transfer from cancer cells to astrocytes in vitro and reduced outgrowth of brain micrometastases in mouse models of breast and lung cancers.
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