Harvard Medical School,
Keywords: microfluidics, tumor, cancer
Summary:Viable tumor-derived circulating tumor cells (CTCs) have been identified in peripheral blood from cancer patients and are not only the origin of intractable metastatic disease but also marker for early cancer. However, the ability to isolate CTCs has proven to be difficult due to the exceedingly low frequency of CTCs in circulation. As a result, their clinical use until recently has been limited to prognosis with limited clinical utility. More recently, we introduced several microfluidic methods to improve the sensitivity of rare event CTC isolation, a strategy that is particularly attractive because it can lead to efficient purification of viable CTCs from unprocessed whole blood. The micropost CTC-Chip (μpCTC-Chip) relies on laminar flow of blood cells through anti-EpCAM antibody-coated microposts, whereas the herringbone CTC-Chip (HbCTC-Chip) uses micro-vortices generated by herringbone-shaped grooves to efficiently direct cells toward antibody-coated surfaces. These antigen-dependent CTC isolation approaches, also called “positive selection”, led to the development of a third technology, which is tumor marker free (or antigen-independent) sorting of CTCs. We call this integrated microfluidic system the CTC-iChip, based on the inertial focusing strategy, which allows positioning of cells in a near-single file line, such that they can be precisely deflected using minimal magnetic force. The major advantage of the microfluidic negative depletion approach stems from the fact that it is based on “negative depletion” of blood cells and hence it is applicable to all solid tumors and does not require tagging or labeling the tumor cells. As a result the CTCs are isolated in pristine conditions and are amenable to analysis using imaging, molecular, and other approaches. We have also identified the presence of CTC clusters, which led to the development of a microchip that is designed to sort clusters of cells from whole blood without any labeling. The propensity of CTC clusters to lead to metastasis is significantly higher than single CTCs, and underlies the importance these cells play in the metastatic cascade. This presentation will share our integrated strategy to simultaneously advance the engineering and microfluidics of CTC-Chip development, the biology of these rare cells, and the potential clinical applications of circulating tumor cells.