Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Lab Chip. 2020 May 7;20(9):1612-1620. doi: 10.1039/d0lc00089b. Epub 2020 Apr 17.
Multicellular clusters in circulation can exhibit a substantially different function and biomarker significance compared to individual cells. Notably, clusters of circulating tumor cells (CTCs) are much more effective initiators of metastasis than single CTCs, and correlate with worse patient prognoses. Measuring the cell-cell adhesion strength of CTC clusters is a critical step towards understanding their subsistence in the circulation and mechanism of elevated tumorigenicity. However, measuring cell-cell adhesion forces in flow is elusive using existing methods. Here, we report an oscillatory inertial microfluidics system which exerts a repeating fluidic force profile on suspended cell doublets to determine their cell-cell adhesion strength (F), without any biophysical modifications to the cell surface and physiological morphology. Using our system, we analyzed a large number (N > 500) of doublets from a patient-derived breast cancer CTC line. We discovered that the cell-cell adhesion strength of CTC doublets varied almost 20-fold between the weakly adhered (F < 28 nN) and strongly bound subpopulations (F > 542 nN). Our system can be used with other cancer or noncancer cells without restrictions, and may be used for rapid screening of drugs aiming to disrupt the highly-metastatic CTC clusters in circulation.
循环中的多细胞簇与单个细胞相比，其功能和生物标志物意义可能有很大的不同。值得注意的是，循环肿瘤细胞（CTC）簇比单个 CTC 更有效地引发转移，并且与患者预后更差相关。测量 CTC 簇的细胞间粘附强度是理解它们在循环中生存和提高肿瘤发生机制的关键步骤。然而，使用现有方法在流动中测量细胞间粘附力是难以实现的。在这里，我们报告了一种振荡惯性微流控系统，该系统对悬浮的细胞对施加重复的流体力模式，以确定它们的细胞间粘附强度（F），而无需对细胞表面和生理形态进行任何生物物理修饰。使用我们的系统，我们分析了来自患者来源的乳腺癌 CTC 系的大量（N > 500）细胞对。我们发现，CTC 细胞对的细胞间粘附强度在弱粘附（F < 28 nN）和强结合亚群（F > 542 nN）之间变化近 20 倍。我们的系统可与其他癌症或非癌症细胞一起使用，没有任何限制，并且可用于快速筛选旨在破坏循环中高度转移性 CTC 簇的药物。
