PO.ET02.12 · 实验与分子治疗
靶向 TUBB2B：利用三阴性乳腺癌的脑转移易感性
Targeting TUBB2B: Exploiting brain metastatic vulnerabilities in triple-negative breast cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
乳腺癌仍是癌症相关死亡的主要原因之一，其中脑转移显著导致不良预后。三阴性乳腺癌（TNBC）表现出侵袭性行为、高脑转移发生率以及有限的治疗选择，凸显了针对脑转移易感性的新型策略的迫切需求。
我们近期采用优化的颈内动脉注射方法建立了体内脑转移模型，并整合生物信息学以鉴定转移定植的驱动因素。TUBB2B 是一种参与神经发育过程中轴突导向的 β-微管蛋白亚型，被鉴定为促进 TNBC 脑转移生长的新型基因（He 等，J Exp & Clin Can Res，2025）。与其神经相关功能相一致，TUBB2B 在 TNBC 细胞中的过表达激活星形胶质细胞，后者反过来上调肿瘤细胞中的 TUBB2B，提示一种促进脑转移定植的前馈相互作用。在此，我们进一步评估了靶向 TUBB2B 的治疗潜力，并探究了其在介导脑微环境中 TNBC-基质细胞相互作用中的作用。
方法：建立了患者来源类器官（PDO）模型以评估 TUBB2B 敲低对肿瘤生长和存活的影响。采用三维共培养模型检查癌细胞-星形胶质细胞/神经元的缝隙连接，并使用染料转移实验评估细胞间通讯。开展临床前研究以检验单独抑制 TUBB2B 及其与目前处于 3 期试验中的脑穿透性 Akt 抑制剂（Akti）GDC-0068（Ipatasertib）联合使用的效果。
结果：TUBB2B 敲低在两个独立模型中显著抑制 PDO 生长，并减少 TNBC 细胞与星形胶质细胞之间的染料转移，提示缝隙连接通讯受损。与单药治疗相比，TUBB2B 耗竭与 Akti 联合使用显著降低了 TNBC 细胞活力。正在进行的研究正在临床前动物模型中检验 siTUBB2B-金纳米颗粒与 Akti（GDC-0068 和 Capivasertib）的联合效果。
结论：TUBB2B 在 TNBC 脑转移中发挥关键作用，代表一个有前景的治疗靶点，尤其是在与 Akt 通路抑制联合使用时。这些发现可能为 TNBC 脑转移患者的未来临床策略提供参考。
本工作由国家自然科学基金（81972781、82273470）和香港城市大学（9609316、9680348）资助。本摘要使用 AI 辅助工具进行了校对。
查看英文原文 English abstract
Breast cancer remains a leading cause of cancer-related mortality, with brain metastasis contributing significantly to poor outcomes. Triple-negative breast cancer (TNBC) exhibits aggressive behavior, a high incidence of brain metastasis, and limited therapeutic options, underscoring the urgent need for novel strategies targeting brain metastatic vulnerabilities.
We recently established an in vivo brain metastasis model using an optimized intracarotid injection method and integrated bioinformatics to identify drivers of metastatic colonization. TUBB2B, a beta-tubulin isoform involved in axon guidance during neural development, was identified as a novel TNBC gene promoting brain metastatic outgrowth (He et. al. J Exp & Clin Can Res, 2025). In line with its neural-related functions, TUBB2B overexpression in TNBC cells activates astrocytes, which in turn upregulate TUBB2B in tumor cells, suggesting a feed-forward interaction that promotes brain metastatic colonization. Here, we further evaluated the therapeutic potential of targeting TUBB2B and investigated its role in mediating TNBC-stromal cell interactions in the brain niche.
Methods: Patient-derived organoid (PDO) models were established to evaluate TUBB2B knockdown effects on tumor growth and survival. 3D co-culture models were employed to examine carcinoma-astrocyte/neuron gap junctions and dye transfer assays were used to assess intercellular communication. Preclinical studies were performed to test the effect of TUBB2B inhibition alone and in combination with the brain-penetrant Akt inhibitor (Akti) GDC-0068 (Ipatasertib), currently in Phase 3 trials.
Results: TUBB2B knockdown significantly inhibited PDO growth in two independent models and reduced dye transfer between TNBC cells and astrocytes, suggesting impaired gap junction communication. Combining TUBB2B depletion with Akti markedly reduced TNBC cell viability compared to single-agent treatment. Ongoing studies are testing the combination effects of siTUBB2B-gold nanoparticles with Akti (GDC-0068 and Capivasertib) in preclinical animal models.
Conclusions: TUBB2B plays a critical role in TNBC brain metastasis and represents a promising therapeutic target, particularly in combination with Akt pathway inhibition. These findings may inform future clinical strategies for TNBC patients with brain metastases.
This work is supported by National Natural Science Foundation of China (81972781, 82273470) and City University of Hong Kong (9609316, 9680348). This abstract was proofread using AI-assisted tools.
利益披露 Disclosure
Q. He, None..
J. Hu, None..
G. M. Tse, None..
J. Y. Tsang, None..
P. Lo, None..
C. Lau, None..
Y. Chin, None.