【佳学基因检测】连接蛋白通过促进 FAK 激活来协调乳腺癌向大脑转移的进展

肿瘤基因疗法说明

开会学习《肿瘤基因突变度与预防策略的实施计划》《Sci Transl Med》在. 2022 Sep 7;14(661):eaax8933.发表了一篇题目为《连接蛋白通过促进 FAK 激活来协调乳腺癌向大脑转移的进展》肿瘤靶向药物治疗基因检测临床研究文章。该研究由Girieca Lorusso, Christof B Wyss, François Kuonen, Nicola Vannini, Clotilde Billottet, Nathalie Duffey, Raphael Pineau, Qiang Lan, Pratyaksha Wirapati, David Barras, Alessandro Tancredi, Ruth Lyck, Hans-Anton Lehr, Britta Engelhardt, Mauro Delorenzi, Andreas Bikfalvi, Curzio Rüegg 等完成。促进了肿瘤的正确治疗与个性化用药的发展，进一步强调了基因信息检测与分析的重要性。

肿瘤靶向药物及正确治疗临床研究内容关键词：

肿瘤靶向治疗基因检测临床应用结果

脑转移是晚期乳腺癌患者发病率增加的并发症。这是一种以生活质量迅速下降和预后不良为特征的严重疾病。临床迫切需要开发有效的疗法来预防和治疗脑转移。在这里，我们描述了一种独特且稳健的小鼠乳腺癌脑转移 (4T1-BM2) 自发临床前模型，该模型有助于揭示指导脑转移传播和定植的分子机制。关键的实验结果在额外的鼠 D2A1-BM2 模型和人类 MDA231-BrM2 模型中得到验证。基因表达分析和功能研究，再加上临床转录组学和组织病理学研究，将连接蛋白 (Cxs) 和粘着斑激酶 (FAK) 确定为协调大脑乳腺癌定植的主要分子。 Cx31 促进同型肿瘤细胞粘附、异型肿瘤-星形胶质细胞相互作用和 FAK 磷酸化。 FAK 信号促进 NF-κB 激活，诱导 Lamc2 表达和层粘连蛋白 332（层粘连蛋白 5）沉积、α6 整合素介导的粘附以及脑实质内的持续存活和生长。在 MDA231-BrM2 模型中，人类同源分子 CX43、LAMA4 和 α3 整合素参与其中。用 FAK 抑制剂进行全身治疗可减少脑转移进展。总之，我们报告了乳腺癌脑转移的自发模型，并确定 Cx 介导的 FAK-NF-κB 信号传导是促进脑定植的细胞自主和微环境控制的细胞存活的机制。考虑到癌症患者脑转移性疾病的治疗选择有限，我们建议将 FAK 作为治疗候选者在临床上进一步追求。

肿瘤发生与反复转移国际数据库描述：

Brain metastasis is a complication of increasing incidence in patients with breast cancer at advanced disease stage. It is a severe condition characterized by a rapid decline in quality of life and poor prognosis. There is a critical clinical need to develop effective therapies to prevent and treat brain metastases. Here, we describe a unique and robust spontaneous preclinical model of breast cancer metastasis to the brain (4T1-BM2) in mice that has been instrumental in uncovering molecular mechanisms guiding metastatic dissemination and colonization of the brain. Key experimental findings were validated in the additional murine D2A1-BM2 model and in human MDA231-BrM2 model. Gene expression analyses and functional studies, coupled with clinical transcriptomic and histopathological investigations, identified connexins (Cxs) and focal adhesion kinase (FAK) as master molecules orchestrating breast cancer colonization of the brain. Cx31 promoted homotypic tumor cell adhesion, heterotypic tumor-astrocyte interaction, and FAK phosphorylation. FAK signaling prompted NF-κB activation inducing Lamc2 expression and laminin 332 (laminin 5) deposition, α6 integrin-mediated adhesion, and sustained survival and growth within brain parenchyma. In the MDA231-BrM2 model, the human homologous molecules CX43, LAMA4, and α3 integrin were involved. Systemic treatment with FAK inhibitors reduced brain metastasis progression. In conclusion, we report a spontaneous model of breast cancer metastasis to the brain and identified Cx-mediated FAK-NF-κB signaling as a mechanism promoting cell-autonomous and microenvironmentally controlled cell survival for brain colonization. Considering the limited therapeutic options for brain metastatic disease in cancer patients, we propose FAK as a therapeutic candidate to further pursue in the clinic.