摘要：SummaryBrain metastasis is an ineffective process, and many cancer cells enter into an indolent state following extravasation in the brain. Single cell RNA sequencing of melanoma brain metastases reveals that non-proliferating brain metastatic melanoma cells exhibit a pattern of gene expression associated with inhibition of DNA methyltransferase 1 (DNMT1). The brain microenvironment, specifically the combination of reactive astrocytes and mechanically soft surroundings, suppressed DNMT1 expression in various cancer types and caused cell cycle delay. Somewhat unexpectedly, we find that DNMT1 suppression not only induces cell cycle delay but also activates pro-survival signals in brain metastatic cancer cells, includingL1CAMandCRYAB. Our results demonstrate that transcriptional changes triggered by DNMT1 suppression is a key step for cancer cells to survive in the brain microenvironment and that they also restrict cancer cell proliferation. The dual consequences of DNMT1 suppression can explain the persistence of indolent cancer cells in the brain microenvironment.Graphical AbstractDisplay OmittedHighlights•Indolence of brain metastatic melanoma cells is associated with DNMT1 inhibition•Reactive astrocytes and mechanically soft surroundings suppress DNMT1 expression•DNMT1 suppression dually activates pro-survival and anti-proliferative signals•DNMT1-αB crystallin axis supports the survival of indolent brain metastatic cellsBiological Sciences; Cell Biology; Cancer; Transcriptomics
