Silvani Giulia, Kopecky Chantal, Romanazzo Sara, Rodríguez Vanina, Das Ayan, Pandzic Elvis, Lock John G, Chaffer Christine L, Poole Kate, Kilian Kristopher A
School of Materials Science and Engineering, UNSW, Sydney, NSW, Australia.
School of Chemistry, Australian Centre for NanoMedicine (ACN), UNSW, Sydney, NSW, Australia.
Nat Commun. 2025 Sep 1;16(1):8160. doi: 10.1038/s41467-025-63374-6.
Metastasis is responsible for most cancer-related deaths. However, only a fraction of circulating cancer cells succeed in forming secondary tumours, indicating that adaptive mechanisms during circulation play a part in dissemination. Here, we report that constriction during microcapillary transit triggers reprogramming of melanoma cells to a tumorigenic cancer stem cell-like state. Using a microfluidic device mimicking physiological flow rates and gradual capillary narrowing, we show that compression through narrow channels causes cell and nuclear deformation, rapid chromatin remodelling and increased calcium signalling via mechanosensor PIEZO1. Within minutes, cells upregulate transcripts associated with metabolic reprogramming and metastatic processes. Over time, this results in the stable adoption of a cancer stem cell-like state. Squeezed cells express elevated melanoma stem cell markers, exhibit increased trans-endothelium invasion and display enhanced tumorigenicity in vitro and in vivo. Pharmacological inhibition of PIEZO1 blocks this transition, while activation with Yoda1 induces the stem cell-like state irrespective of constriction. Deletion of PIEZO1 completely abolishes the constriction-induced phenotype. Together, these findings demonstrate that compressive forces during circulation reprogram circulating cancer cells into tumorigenic, stem cell-like states, primed for extravasation and metastatic colonization.
转移是大多数癌症相关死亡的原因。然而，只有一小部分循环癌细胞能够成功形成继发性肿瘤，这表明循环过程中的适应性机制在肿瘤扩散中起作用。在此，我们报告微毛细血管转运过程中的收缩会触发黑色素瘤细胞重编程为具有致瘤性的癌症干细胞样状态。使用模拟生理流速和逐渐变窄的毛细血管的微流控装置，我们发现通过狭窄通道的压缩会导致细胞和细胞核变形、快速的染色质重塑以及通过机械传感器PIEZO1增加钙信号传导。在几分钟内，细胞会上调与代谢重编程和转移过程相关的转录本。随着时间的推移，这会导致稳定地转变为癌症干细胞样状态。受到挤压的细胞会高表达黑色素瘤干细胞标志物，表现出增强的跨内皮侵袭能力，并在体外和体内显示出更强的致瘤性。对PIEZO1的药理学抑制会阻断这种转变，而用Yoda1激活则会诱导干细胞样状态，无论是否存在收缩。删除PIEZO1会完全消除收缩诱导的表型。总之，这些发现表明循环过程中的压缩力会将循环癌细胞重编程为具有致瘤性的干细胞样状态，为外渗和转移定植做好准备。
