Brain metastasis is a major cause of cancer mortality, but its molecular mechanisms are severely understudied. In addition, little is known regarding the role of m⁶A reader YTHDF3 in human diseases. Here, we show that YTHDF3 overexpression clinically correlates with brain metastases in breast cancer patients. YTHDF3 promotes cancer cell interactions with brain endothelial cells and astrocytes, blood-brain barrier extravasation, angiogenesis, and outgrow. Mechanistically, YTHDF3 enhances the translation of m⁶A-enriched transcripts for ST6GALNAC5, GJA1, and EGFR, all associated with brain metastasis. Furthermore, overexpression of YTHDF3 in brain metastases is attributed to increased gene copy number and the autoregulation of YTHDF3 cap-independent translation by binding to m⁶A residues within its own 5′ UTR. Our work uncovers an essential role of YTHDF3 in controlling the interaction between cancer cells and brain microenvironment, thereby inducing brain metastatic competence.

脑转移是癌症死亡的主要原因，但其分子机制尚未得到充分研究。此外，关于 m ⁶ A 阅读器 YTHDF3 在人类疾病中的作用知之甚少。在这里，我们显示 YTHDF3 过表达在临床上与乳腺癌患者的脑转移相关。YTHDF3 促进癌细胞与脑内皮细胞和星形胶质细胞的相互作用、血脑屏障外渗、血管生成和生长。从机制上讲，YTHDF3 增强了富含m ⁶ A 的 ST6GALNAC5、GJA1 和 EGFR 转录本的翻译，所有这些都与脑转移有关。此外，YTHDF3 在脑转移灶中的过表达归因于基因拷贝数的增加和 YTHDF3 通过与 m⁶ A 残基在其自身的 5' UTR 内。我们的工作揭示了 YTHDF3 在控制癌细胞与脑微环境之间的相互作用中的重要作用，从而诱导脑转移能力。