Transcription profiles of 231-BM cells with vs without circADAMTS12 depletion.

Brain metastases are a lethal complication in cancer patients without effective therapies, and brain-resident microglia are an essential and universal component of the anti-inflammatory, protumorigenic tumor-associated macrophages (TAMs) in the brain tumor microenvironment (TME). However, whether and how microglia are directed to adopt an anti-inflammatory phenotype to support metastatic colonization in the brain remains unclear. Here, using the breast to brain metastasis (B2BM) model, we report that a circular RNA (circADAMTS12) expressed in B2BM cells is required for brain metastasis development, and that circADAMTS12, but not its linear transcript, is necessary and sufficient to promote cancer cell colonization of brain tissue. Mechanistically, circADAMTS12 tilts the microglial fate balance toward an anti-inflammatory phenotype by effectively inducing cancer cells to express various cytokines, including the pro-inflammatory cytokine.