Abstract
Cancer mortality mainly arises from metastases, due to cells that escape from a primary tumor, circulate in the blood as circulating tumor cells (CTCs), permeate across blood vessels and nest in distant organs. It is still unclear how CTCs overcome the harsh conditions of fluid shear stress and mechanical constraints within the microcirculation. Here, a minimal model of the blood microcirculation was established through the fabrication of microfluidic channels comprising constrictions. Metastatic breast cancer cells of epithelial-like and mesenchymal-like phenotypes were flowed into the microfluidic device. These cells were visualized during circulation and analyzed for their dynamical behavior, revealing long-lived plastic deformations and significant differences in biomechanics between cell types. γ-H2AX staining of cells retrieved post-circulation showed significant increase of DNA damage response in epithelial-like SK-BR-3 cells, while gene expression analysis of key regulators of epithelial-to-mesenchymal transition revealed significant changes upon circulation. This work thus documents first results of the changes at the cellular, subcellular and molecular scales induced by the two main mechanical stimuli arising from circulatory conditions, and suggest a significant role of this still elusive step of the metastatic cascade in cancer cells heterogeneity and aggressiveness.
Highlights
Understanding the process of metastasis is a major challenge in the fight against cancer
Numerous studies have revealed important influences of mechanical constraints in cancer[6], surprisingly only a few works explored the responses of cancer cells to the mechanical stressors provided by the blood circulation, and most of them were limited to the study of the effect of shear stress
Either poorly (SK-BR-3) or highly (MDA-MB-231) metastatic breast cancer cell lines were delivered into these five types of geometric microfluidic models, for single cell mechanical phenotyping (Supplementary Fig. S3)
Summary
Understanding the process of metastasis is a major challenge in the fight against cancer This process is a multi-step one that often involves cells migrating from a primary tumor (at 90% of epithelial origin, i.e. carcinomas) into the blood stream (intravasation), where they reach a distant organ by re-crossing the endothelial barrier (extravasation). The acquisition and maintenance of the mesenchymal phenotype, a key to the metastatic process require important cellular reprogramming by the activation of master regulators including transcription factors such as Snail, Twist and zinc-finger E-box-binding (ZEB), and transforming growth factor, TGF-β17,18 These phenotypic changes, are not bimodal, and recent studies suggest that disseminating tumor cells may present diverse and heterogeneous combinations of epithelial and mesenchymal phenotypic traits[14,19,20]. It should be considered as an active step that is likely to modify gene expression of CTCs and possibly their mechanical properties
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