Department of Oncology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, China.
Breast Cancer Res. 2023 Apr 17;25(1):43. doi: 10.1186/s13058-023-01642-3.
Triple-negative breast cancer (TNBC) exhibits the poorest outcomes among breast cancer subtypes due to the high heterogeneity and a lasting scarcity of effectual treatments. Targeted therapies based on molecular subtypes of TNBC are critical step toward tailoring treatments to improve clinical outcomes. Gastrointestinal cancer stem cell (CSC) marker DCLK1 was reported to be highly expressed in stem cell-rich subtype of TNBC. Here, we firstly explored the impacts of DCLK1 on tumor cells as well as their immune microenvironment in TNBC and potential therapeutic strategies for TNBC patients with high DCLK1 expression. Our results disclosed that DCLK1 overexpression promoted, while knockout of DCLK1 suppressed the CSC-like traits of TNBC cells and resistance to chemotherapeutics. Besides, DCLK1 supported immune escape by inhibiting intratumoral cytotoxic T cell infiltration in TNBC and hence limited immune checkpoint inhibitors efficacy. Mechanistically, bioinformatics analysis revealed that IL-6/STAT3 signaling was significantly enriched in high DCLK1-expressing patients, and our results further revealed that DCLK1 enhanced IL-6 expression and STAT3 activation in TNBC cells, which finally gave rise to upregulated CSC traits and suppressed CD8+ T-cell activity. Inhibiting IL-6/STAT3 pathway by IL-6R antagonist, Tocilizumab or STAT3 inhibitor, S31-201 could abolish DCLK1-promoted malignant phenotypes of TNBC cells. Finally, DCLK1 was identified to be specifically and highly expressed in the mesenchymal-like subtype of TNBC and targeting DCLK1 could improve chemotherapy efficacy and activate antitumor immunity. Overall, our study revealed the potential clinical benefits of targeting DCLK1 in TNBC treatment.
三阴性乳腺癌（TNBC）由于高度异质性和持久缺乏有效治疗方法，其预后在乳腺癌亚型中最差。基于 TNBC 分子亚型的靶向治疗是实现治疗个体化以改善临床结局的关键步骤。胃肠道癌症干细胞（CSC）标志物 DCLK1 被报道在富含干细胞的 TNBC 亚型中高度表达。在这里，我们首先探讨了 DCLK1 对 TNBC 肿瘤细胞及其免疫微环境的影响，以及针对 DCLK1 高表达的 TNBC 患者的潜在治疗策略。我们的结果表明，DCLK1 过表达促进，而 DCLK1 敲除则抑制 TNBC 细胞的 CSC 样特征和对化疗药物的耐药性。此外，DCLK1 通过抑制 TNBC 中肿瘤内细胞毒性 T 细胞浸润来促进免疫逃逸，从而限制免疫检查点抑制剂的疗效。从机制上讲，生物信息学分析表明，IL-6/STAT3 信号在高 DCLK1 表达的患者中显著富集，我们的结果进一步表明，DCLK1 增强了 TNBC 细胞中 IL-6 的表达和 STAT3 的激活，最终导致 CSC 特征上调和 CD8+T 细胞活性受抑制。通过 IL-6R 拮抗剂、托珠单抗或 STAT3 抑制剂 S31-201 抑制 IL-6/STAT3 通路可以消除 DCLK1 促进的 TNBC 细胞恶性表型。最后，DCLK1 被鉴定为在 TNBC 的间质样亚型中特异性和高度表达，靶向 DCLK1 可以提高化疗疗效并激活抗肿瘤免疫。总的来说，我们的研究揭示了靶向 DCLK1 在 TNBC 治疗中的潜在临床获益。
