Microfluidic Tandem Mechanical Sorting System for Enhanced Cancer Stem Cell Isolation and Ingredient Screening

Abstract Robust isolation of cancer stem cells (CSCs) in a high‐throughput, label‐free manner is critical for understanding tumor heterogeneity and developing therapeutic strategies targeting CSCs. Cell‐mechanics‐based microfluidic sorting systems provide efficient and specific platforms for investigation of stem cell‐like characteristics on the basis of cell deformability and cell‐substrate adhesion properties. In the present study, a microfluidic tandem mechanical sorting system is developed to enrich CSCs with high flexibility and low adhesive capacity. In the integrated microfluidic system, cancer cells are driven by hydrodynamic forces to flow continuously through two featured devices, which are functionalized with sequentially variable microbarriers and surface‐coated fluid mixing microchannels, respectively. Collected deformable and low‐adhesive cancer cells exhibit enhanced stem cell‐like properties with higher stemness and metastasis capacity both in vitro and in vivo, compared with each single device separation. Using these devices, bioactive natural compound screening targeting CSCs is performed and a potent therapeutic compound isoliquiritigenin from licorice is identified to inhibit the lung cancer stem cell phenotype. Taken together, this microfluidic tandem mechanical sorting system can facilitate drug screening targeting CSCs and the analysis of signals regulating CSC function in drug resistance.