Biomechanical Phenotyping of Circulating Tumor Cells: A Window to Study Cancer Metastasis

原发性和转移性肿瘤都有血源性肿瘤细胞脱落，它们被认为有助于癌症向身体远处扩散。因此，为了预测肿瘤对治疗的反应，人们对使用血液样本来捕获和测量循环肿瘤细胞的特性非常感兴趣。尽管它们很重要，但目前对循环肿瘤细胞的了解却非常少。该项目将建造一种新型设备，将这些细胞从血液中分离出来，并快速测量它们的生物和生物力学特性。除了分离和测量肿瘤细胞特性外，该装置还可以用于分离和测量血液中的其他细胞成分，并使用该装置进行机械测量。这项研究将对不同教育水平、性别和种族的学生产生广泛的影响，让他们接触到与我们社会相关的科学和工程领域令人兴奋的挑战。在理解循环肿瘤细胞的生物学，并最终提高对癌症血液转移的系统水平理解方面，这仍然是一个主要的挑战。本研究将通过建立一种细胞分选装置，在不使用任何捕获抗体的情况下有效地捕获和分离循环肿瘤细胞，解决理解循环肿瘤细胞生物学性质的挑战。微流控可变形性微细胞仪阵列也将被开发用于高通量多参数单细胞生化和生物力学表型的活的单个循环肿瘤细胞。可变形性微细胞仪的实验结果将进一步用于指导接触单元/内聚区模型和有限元模拟的发展，以量化循环肿瘤细胞的细胞刚度和表面抗原的表达水平。研究小组将进一步将这些技术平台与临床前小鼠异种移植模型结合起来，研究循环肿瘤细胞从原发肿瘤中释放的时间、异质性以及生物力学和生化特性。

Blood-borne cancerous tumor cells are shed by both primary and metastatic tumors and they are thought to contribute to the spread of cancer to distant sites in the body. There is, therefore, a great interest in using a blood sample to capture and measure the properties of circulating tumor cells in order to predict the response of the tumor to therapy. Despite their importance, the current understanding of circulating tumor cells is extremely poor. This project will build a novel device that will separate these cells from the blood and rapidly measure their biological and biomechanical properties. The developed device will be useful beyond the isolation and measurement of tumor cell properties, as the other cellular components of blood could also be separated and mechanically measured using the device. The research will have broad impacts on students from different educational levels and genders and ethnicities, by exposing them to exciting challenges in science and engineering that have relevance to our society.It still remains a major challenge in understanding the biology of circulating tumor cells, and ultimately, improving the systems level understanding of blood-borne metastasis in cancer. This research will address the challenge in understanding the biological nature of circulating tumor cells by establishing a cell sorting device that can efficiently capture and isolate the circulating tumor cells without using any capture antibody. A microfluidic deformability microcytometer array will also be developed for high-throughput multiparametric single-cell biochemical and biomechanical phenotyping of live single circulating tumor cells. Experimental results from the deformability microcytometer will be further used to guide developments of a contact element / cohesive zone model and finite element simulation for quantifications of cell stiffness and expression levels of surface antigens of circulating tumor cells. The research team will further integrate the technological platforms with preclinical murine xenograft models to investigate the timing of circulating tumor cell release from primary tumors and their heterogeneity and biomechanical and biochemical properties.