Abstract
The three main challenges of cancer treatment are metastases, recurrence, and acquired therapy resistance. These challenges have been closely linked to circulating cancer cell clusters. A detailed understanding of their genetic and morphological composition is essential. This will not only improve our knowledge of basic cancer biology but enable the successful development of much needed therapies preventing the three main challenges mentioned above. Extensive research effort is underway to isolate, capture, and analyze circulating tumor cells. However, few if any current efforts specifically target cancer cell clusters, and their much greater ability to initiate new tumors. Growing scientific consensus over the last five years has convincingly established the importance of targeting circulating cancer cell clusters verses individual CTCs to prevent the occurrence of metastatic disease. Based on the increased clinical importance of cancer cell clusters as the main driver of cancer metastasis, new and improved methods are much needed to access these larger multi-celled structures. Microfluidic devices offer a readily accessible platform for a customizable microenvironment for cell isolation and analysis. In this study, we show how a well-known passive micromixer design (staggered herringbone mixer - SHM) can be optimized to induce maximum chaotic advection within antibody-coated channels of dimensions appropriate for the capture of cancer cell clusters. The device’s principle design configuration is called: Single-Walled Staggered Herringbone (SWaSH). The preliminary empirical results of our work show that utilization of extensive simulation and modeling can accelerate the development of a working prototype that allows for target-specific cancer cell cluster isolation.
Highlights
The fight against metastatic cancer is among the foremost challenges we face in our efforts to truly improve patient outcomes of many if not most forms of cancer
Our goal was to target rare circulating tumor cells (CTC) clusters with a size ranging between 50-150 μm in diameter (∼2-50 cells per cluster) based on the cluster sizes identified in patients and described in the literature
Capture, and characterization of CTCs and CTC clusters from patients’ whole blood is a tremendously important milestone in the comprehensive understanding of their role in the pathology of most cancers. Analysis of these extremely rare cancer cells is an essential step in the development of new targeted therapies for these malignancies
Summary
The fight against metastatic cancer is among the foremost challenges we face in our efforts to truly improve patient outcomes of many if not most forms of cancer. The identification of circulating cancer cell clusters as primary vehicles of the metastatic process have opened up a new therapeutic target space holding great promise. This is confirmed by the most recent findings by Aceto and colleagues clearly showing that eliminating circulating cancer cell clusters directly impacts metastatic potential in an orthotopic patient-derived-xenograft models of breast cancer. Microfluidic technologies hold great promise in cancer diagnosis, monitoring of disease progression, and potentially, identification of optimized therapy.. Most of these methods focus on individual circulating tumor cells (CTC) and often exhibit an intrinsic bias against larger multicellular structures.. The authors commented on the intrinsic bias of the utilized approach against clusters of a larger size.. Maintaining the viability of the isolated cancer cell clusters will allow more relevant analysis of their tumorigenic potential and enable cutting edge downstream analysis
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