The Brain Microenvironment Induces DNMT1 Suppression and Indolence of Metastatic Cancer Cells
The Brain Microenvironment Induces DNMT1 Suppression and Indolence of Metastatic Cancer Cells
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DOI：
10.1016/j.isci.2020.101480
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发表时间：
2020-09-25
期刊：
影响因子：
5.8
通讯作者：
Sahai, Erik
中科院分区：
文献类型：
--
作者：
Hirata, Eishu;Ishibashi, Kojiro;Sahai, Erik
脑转移是一个无效的过程，许多癌细胞在脑内外渗后进入惰性状态。黑色素瘤脑转移的单细胞RNA测序显示，非增殖性脑转移性黑色素瘤细胞表现出与DNA甲基转移酶1 （DNMT1）抑制相关的基因表达模式。脑微环境，特别是反应性星形胶质细胞与机械软环境的结合，抑制了各种癌症类型中DNMT1的表达，并导致细胞周期延迟。出乎意料的是，我们发现DNMT1抑制不仅会导致细胞周期延迟，还会激活脑转移癌细胞中的促生存信号，包括L1CAM和CRYAB。我们的研究结果表明，DNMT1抑制引发的转录变化是癌细胞在脑微环境中存活的关键步骤，它们也限制了癌细胞的增殖。DNMT1抑制的双重后果可以解释惰性癌细胞在脑微环境中的持续存在。
Brain 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, including L1CAM and CRYAB. 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.