Department of Chemical Engineering and Materials Science, University of Minnesota, Minneapolis, Minnesota.
Division of Hematology and Oncology, Department of Medicine, Tisch Cancer Institute, Black Family Stem Cell Institute, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
Biotechnol Bioeng. 2020 Oct;117(10):3066-3080. doi: 10.1002/bit.27479. Epub 2020 Jul 9.
Around 20-30% of ovarian cancer patients exhibit chemoresistance, but there are currently no methods to predict whether a patient will respond to chemotherapy. Here, we discovered that chemoresistant ovarian cancer cells exhibit enhanced survival in a quiescent state upon experiencing the stress of physical confinement. When immobilized in stiff silica gels, most ovarian cancer cells die within days, but surviving cells exhibit hallmarks of single-cell dormancy. Upon extraction from gels, the cells resume proliferation but demonstrate enhanced viability upon reimmobilization, indicating that initial immobilization selects for cells with a higher propensity to enter dormancy. RNA-seq analysis of the extracted cells shows they have signaling responses similar to cells surviving cisplatin treatment, and in comparison to chemoresistant patient cohorts, they share differentially expressed genes that are associated with platinum-resistance pathways. Furthermore, these extracted cells demonstrate greater resistance to cisplatin and paclitaxel, despite being proliferative. In contrast, serum starvation and hypoxia could not effectively select for chemoresistant cells upon removal of the environmental stress. These findings demonstrate that ovarian cancer chemoresistance and the ability to enter dormancy are linked, and immobilization rapidly distinguishes chemoresistant cells. This platform could be suitable for mechanistic studies, drug development, or as a clinical diagnostic tool.
约 20-30%的卵巢癌患者表现出化疗耐药性，但目前尚无方法预测患者对化疗的反应。在这里，我们发现，在经历物理限制的压力时，耐药性卵巢癌细胞在静止状态下表现出更强的生存能力。当固定在坚硬的硅胶中时，大多数卵巢癌细胞在几天内死亡，但存活的细胞表现出单细胞休眠的特征。从凝胶中提取后，细胞恢复增殖，但重新固定时表现出更高的活力，表明初始固定选择了更倾向于进入休眠的细胞。对提取细胞的 RNA-seq 分析表明，它们具有与顺铂治疗后存活的细胞相似的信号反应，与耐药性患者队列相比，它们具有与铂耐药途径相关的差异表达基因。此外，尽管这些提取的细胞具有增殖能力，但它们对顺铂和紫杉醇的耐药性更强。相比之下，血清饥饿和缺氧在去除环境压力后不能有效地选择耐药细胞。这些发现表明，卵巢癌化疗耐药性和进入休眠的能力是相关的，并且固定可以快速区分耐药细胞。该平台可适用于机制研究、药物开发或作为临床诊断工具。
