Mechanobiology Institute, National University of Singapore, Singapore, 117411, Singapore.
Institute for Health Innovation and Technology (iHealthtech), National University of Singapore, Singapore, 119276, Singapore.
Adv Sci (Weinh). 2023 Aug;10(22):e2201663. doi: 10.1002/advs.202201663. Epub 2023 May 23.
Cancer cells in secondary tumors are found to form metastases more efficiently as compared to their primary tumor counterparts. This is partially due to the unfavorable microenvironments encountered by metastasizing cancer cells that result in the survival of a more metastatic phenotype from the original population. However, the role of deleterious mechanical stresses in this change of metastatic potential is unclear. Here, by forcing cancer cells to flow through small capillary-sized constrictions, it is demonstrated that mechanical deformation can select a tumor cell subpopulation that exhibits resilience to mechanical squeezing-induced cell death. Transcriptomic profiling reveals up-regulated proliferation and DNA damage response pathways in this subpopulation, which are further translated into a more proliferative and chemotherapy-resistant phenotype. These results highlight a potential link between the microenvironmental physical stresses and the enhanced malignancy of metastasizing cancer cells which may be utilized as a therapeutic strategy in preventing the metastatic spread of cancer cells.
相比原发性肿瘤细胞，继发性肿瘤中的癌细胞更易形成转移灶。这部分是由于转移癌细胞遇到了不利的微环境，导致原始细胞群中更具转移性的表型存活下来。然而，机械应力的有害作用在这种转移潜能的改变中所扮演的角色尚不清楚。在这里，通过迫使癌细胞流过小毛细血管大小的狭窄通道，可以证明机械变形可以选择一个对机械挤压诱导的细胞死亡具有弹性的肿瘤细胞亚群。转录组谱分析显示，该亚群中增殖和 DNA 损伤反应途径上调，进而转化为更具增殖性和化疗耐药性的表型。这些结果强调了微环境物理应激与转移癌细胞恶性程度增强之间的潜在联系，这可能被用作预防癌细胞转移扩散的治疗策略。
