由于对其驱动机制的理解有限，对于大脑转移瘤的有效控制仍然是一个迫切的临床需求。虽然已经描述了乳腺癌向大脑转移过程中神经适应特点的获取，但目前对调节这种神经适应性以及由此产生的大脑转移能力的机制仍知之甚少。在本研究中，我们阐明了神经专一剪接因子Ser/Arg重复基质蛋白4 (SRRM4) 在调节乳腺癌细胞的微环境适应和大脑转移定殖中的作用。我们利用纯神经元培养物、对大脑没有接触的及患者来源的BM肿瘤细胞，以及体内肿瘤模型，在肿瘤细胞中调查了神经适应的早期介质的诱导。当SRRM4在全身性乳腺癌细胞中过表达时，乳腺癌细胞向大脑转移增强，导致体内总生存率较差。与此同时，SRRM4的沉默表达在中枢神经系统转移中并不能提供任何优势。此外，减少乳腺癌细胞中的SRRM4表达会减缓其增殖速度并增加对化疗的抵抗力。相反，当SRRM4/REST4水平升高时，肿瘤细胞在营养匮乏条件下仍然能够保持生长。在神经元共培养中，降低乳腺癌细胞中的SRRM4表达会削弱其适应大脑微环境的能力，而增加SRRM4/REST4水平会导致神经递质和突触信号介质的高度表达，并具有显著的定殖优势。总的来说，我们的研究结果确定了SRRM4作为大脑转移定殖的调控因子，并且为乳腺癌疗法提供了潜在的治疗靶点。© 2023 作者。 版权归牛津大学出版社代表神经肿瘤学会所有。保留所有权利。有关权限，请发送电子邮件至：journals.permissions@oup.com.

Effective control of brain metastasis remains an urgent clinical need due a limited understanding of the mechanisms driving it. Although the gain of neuro-adaptive attributes in breast-to-brain metastases has been described, the mechanisms that govern this neural acclimation and the resulting brain metastasis competency are poorly understood. Herein, we define the role of neural-specific splicing factor Ser/Arg Repetitive Matrix Protein 4 (SRRM4) in regulating microenvironmental adaptation and brain metastasis colonization in breast cancer cells.Utilizing pure neuronal cultures and brain-naïve and patient-derived BM tumor cells, along with in vivo tumor modeling, we surveyed the early induction of mediators of neural acclimation in tumor cells.When SRRM4 is overexpressed in systemic breast cancer cells, there is enhanced breast to brain metastasis leading to poorer overall survival in vivo. Concomitantly, SRRM4 knockdown expression does not provide any advantage in CNS metastasis. In addition, reducing SRRM4 expression in breast cancer cells slows down proliferation and increases resistance to chemotherapy. Conversely, when SRRM4/REST4 levels are elevated, tumor cell growth is maintained even in nutrient-deprived conditions. In neuronal co-culture, decreasing SRRM4 expression in breast cancer cells impairs their ability to adapt to the brain microenvironment, while increasing SRRM4/REST4 levels leads to greater expression of neurotransmitter and synaptic signaling mediators and a significant colonization advantage.Collectively, our findings identify SRRM4 as a regulator of brain metastasis colonization, and a potential therapeutic target in breast cancer.© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.