Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, United States.
Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, United States.
Biomaterials. 2023 Jul;298:122128. doi: 10.1016/j.biomaterials.2023.122128. Epub 2023 Apr 21.
Multicellular clustering provides cancer cells with survival advantages and facilitates metastasis. At the tumor migration front, cancer cell clusters are surrounded by an aligned stromal topography. It remains unknown whether aligned stromal topography regulates the resistance of migrating cancer cell clusters to therapeutics. Using a hybrid nanopatterned model to characterize breast cancer cell clusters at the migration front with aligned stromal topography, we demonstrate that topography-induced migrating cancer cell clusters exhibit upregulated cytochrome P450 family 1 (CYP1) drug metabolism and downregulated glycolysis gene signatures, which correlates with unfavorable prognosis. Screening on approved oncology drugs shows that cancer cell clusters on aligned stromal topography are more resistant to diverse chemotherapeutics. Full-dose drug testings further indicate that topography induces drug resistance of hormone receptor-positive breast cancer cell clusters to doxorubicin and tamoxifen and triple-negative breast cancer cell clusters to doxorubicin by activating the aryl hydrocarbon receptor (AhR)/CYP1 pathways. Inhibiting the AhR/CYP1 pathway restores reactive oxygen species-mediated drug sensitivity to migrating cancer cell clusters, suggesting a plausible therapeutic direction for preventing metastatic recurrence.
细胞簇聚为癌细胞提供了生存优势，并促进了转移。在肿瘤迁移前沿，癌细胞簇被排列整齐的基质地形所包围。目前尚不清楚排列整齐的基质地形是否调节了迁移癌细胞簇对治疗的耐药性。本研究使用混合纳米图案模型来描述具有排列整齐的基质地形的迁移前沿的乳腺癌细胞簇，结果表明，拓扑结构诱导的迁移癌细胞簇表现出上调的细胞色素 P450 家族 1（CYP1）药物代谢和下调的糖酵解基因特征，这与不良预后相关。对已批准的肿瘤学药物进行筛选表明，排列整齐的基质地形上的癌细胞簇对多种化疗药物的耐药性更强。全剂量药物测试进一步表明，拓扑结构通过激活芳香烃受体（AhR）/CYP1 途径诱导激素受体阳性乳腺癌细胞簇对阿霉素和他莫昔芬以及三阴性乳腺癌细胞簇对阿霉素的耐药性。抑制 AhR/CYP1 途径可恢复迁移癌细胞簇对活性氧介导的药物敏感性，提示了一种预防转移性复发的合理治疗方向。
