The Oncology Institute "Prof. Dr. Ion Chiricuta", Department of Genetics, Genomics and Experimental Pathology, 34-36 Republicii Street, Cluj-Napoca, Romania; "Babes-Bolyai" University, Department of Molecular Biology and Biotechnology, 1 Mihail Kogalniceanu Street, Cluj-Napoca, Romania.
The Oncology Institute "Prof. Dr. Ion Chiricuta", Department of Genetics, Genomics and Experimental Pathology, 34-36 Republicii Street, Cluj-Napoca, Romania.
Life Sci. 2024 Oct 1;354:122982. doi: 10.1016/j.lfs.2024.122982. Epub 2024 Aug 14.
While enhanced tumor cell migration is a key process in the tumor dissemination, mechanistic insights into causal relationships between tumor cells and mechanical confinement are still limited. Here we combine the use of microfluidic platforms to characterize confined cell migration with genomic tools to systematically unravel the global signaling landscape associated with the migratory phenotype of breast cancer (BC) cells.
The spontaneous migration capacity of seven BC cell lines was evaluated in 3D microfluidic devices and their migration capacity was correlated with publicly available molecular signatures. The role of identified signaling pathways on regulating BC migration capacity was determined by receptor stimulation through ligand binding or inhibition through siRNA silencing. Downstream effects on cell migration were evaluated in microfluidic devices, while the molecular changes were monitored by RT-qPCR.
Expression of 715 genes was correlated with BC cells migratory phenotype, revealing TNF-α as one of the top upstream regulators. Signal transduction experiments revealed that TNF-α stimulates the confined migration of triple negative, mesenchymal-like BC cells that are also characterized by high TNFR1 expression, but inhibits the migration of epithelial-like cells with low TNFR1 expression. TNFR1 was strongly associated with the migration capacity and triple-negative, mesenchymal phenotype. Downstream of TNF/TNFR1 signaling, transcriptional regulation of NFKB seems to be important in driving cell migration in confined spaces.
TNF-α/TNFR1 signaling axis reveals as a key player in driving BC cells confined migration, emerging as a promising therapeutic strategy in targeting dissemination and metastasis of triple negative, mesenchymal BC cells.
虽然增强的肿瘤细胞迁移是肿瘤扩散的关键过程，但肿瘤细胞与机械限制之间因果关系的机制见解仍然有限。在这里，我们结合使用微流控平台来描述受限的细胞迁移，并利用基因组工具系统地揭示与乳腺癌（BC）细胞迁移表型相关的全局信号景观。
在 3D 微流控设备中评估了七种 BC 细胞系的自发迁移能力，并将其迁移能力与公开可用的分子特征相关联。通过配体结合的受体刺激或通过 siRNA 沉默抑制来确定鉴定的信号通路对调节 BC 迁移能力的作用。通过微流控设备评估对细胞迁移的下游影响，同时通过 RT-qPCR 监测分子变化。
715 个基因的表达与 BC 细胞的迁移表型相关，揭示 TNF-α 是顶级上游调节剂之一。信号转导实验表明，TNF-α 刺激具有高 TNFR1 表达的三阴性、间充质样 BC 细胞的受限迁移，但抑制具有低 TNFR1 表达的上皮样细胞的迁移。TNFR1 与迁移能力和三阴性、间充质表型密切相关。在 TNF/TNFR1 信号下游，NFKB 的转录调节似乎在驱动受限空间中的细胞迁移中很重要。
TNF-α/TNFR1 信号轴揭示为驱动 BC 细胞受限迁移的关键参与者，成为靶向三阴性、间充质 BC 细胞扩散和转移的有前途的治疗策略。
