Abstract：
Brain metastasis (BM) is one of the main causes of death in patients with non-small cell lung carcinoma. The specific pathological processes of BM, which are inextricably linked to the brain tumor microenvironment, such as the abundance of astrocytes, lead to limited treatment options and poor prognosis. Reactive astrocytes are acquired in the BM; however, the underlying mechanisms remain unclear. This study aimed to explore the mechanisms by which astrocytes promote BM development. We determined the crucial role of reactive astrocytes in promoting the proliferation and migration of brain metastatic lung tumor cells by upregulating protocadherin 1 (PCDH1) expression in an in vitro co-culture model. The overexpression of PCDH1 was confirmed in clinical BM samples using immunohistochemical staining. Survival analysis indicated that high-PCDH1 expression was associated with poor survival in patients with lung adenocarcinoma. In vivo assays further showed that silence of PCDH1 effectively inhibited the tumor progression of brain metastases and prolonged the survival of animals. RNA sequencing has revealed that PCDH1 plays an important role in cell proliferation and adhesion. In conclusion, the present study revealed the promoting role of astrocytes in enhancing the aggressive phenotype of brain metastatic tumor cells by regulating the expression of PCDH1, which might be a biomarker for BM diagnosis and prognosis, suggesting the potential efficacy of targeting important astrocyte-tumor interactions in the treatment of patients with non-small cell lung carcinoma with BM.
摘要：
脑转移(BM)是非小细胞肺癌患者死亡的主要原因之一。BM的具体病理过程，这与脑肿瘤微环境密不可分，比如星形胶质细胞的丰度，导致有限的治疗选择和不良预后。反应性星形胶质细胞在BM中获得；然而，潜在机制尚不清楚.本研究旨在探讨星形胶质细胞促进BM发育的机制。我们通过在体外共培养模型中上调原钙粘蛋白1（PCDH1）的表达，确定了反应性星形胶质细胞在促进脑转移性肺肿瘤细胞增殖和迁移中的关键作用。使用免疫组织化学染色在临床BM样品中证实PCDH1的过表达。生存分析表明，PCDH1高表达与肺腺癌患者的低生存率相关。体内测定进一步显示PCDH1的沉默有效抑制脑转移的肿瘤进展并延长动物的存活。RNA测序显示PCDH1在细胞增殖和粘附中起重要作用。总之,本研究揭示了星形胶质细胞通过调节PCDH1的表达在增强脑转移肿瘤细胞侵袭性表型中的促进作用，PCDH1可能是BM诊断和预后的生物标志物。提示靶向重要的星形胶质细胞-肿瘤相互作用在BM非小细胞肺癌患者治疗中的潜在疗效。
