Fluid shear stress coupled with narrow constrictions induce cell type-dependent morphological and molecular changes in circulating tumor cells

Abstract

<jats:title>Abstract</jats:title><jats:p>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 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, analyzed for their dynamical behavior and retrieved post-circulation. γ-H2AX staining 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 increase of Twist2 relative expression in mesenchymal-like MDA-MB-231 cells post-circulation. This work documents first results of the changes at the cellular, subcellular and molecular scales induced by the two main mechanical stimuli arising from circulatory conditions.</jats:p>

Mechanobiology and survival strategies of circulating tumor cells: a process towards the invasive and metastatic phenotype

“…(D) Figure from (Xia et al, 2018) showing: (A) the design of a micro-constriction array with sixteen flow channels (in yellow) and the pneumatic control channels (in brown); (B), a small portion of the pneumatic control part of the device made of three layers: PDMS layer for pneumatic control, PDMS layer for flow channels, and glass substrate; (C) a single patch of the micro-constriction array; and (D) photograph of the fabricated microfluidic device including the fluidic and pneumatic channels. (E) Figure from (Cognart et al, 2020). Schematic designs of microfluidic channels (upper panels) and brightfield images of SK-BR-3 and MDA-MB-231 cells before and while residing in the three types of micro-constrictions at a constant applied pressure of 10 kPa (lower panels).…”

“…They proposed that such studies could guide the optimization of CTC sorting devices (Xia et al, 2018). To examine the effect of different mechanical constrictions caused by geometry on the flow-driven migration of single CTCs, Cognart et al constructed five microfluidic models with five distinct geometries (Cognart et al, 2020). By separately adjusting the pressure, they streamed two metastatic breast cancer cell lines, one mesenchymal-like (MDA-MB-231) and one epithelial-like (SK-BR-3), into the microfluidic device.…”

“…By separately adjusting the pressure, they streamed two metastatic breast cancer cell lines, one mesenchymal-like (MDA-MB-231) and one epithelial-like (SK-BR-3), into the microfluidic device. In all models, MDA-MB-231 cells were more deformable than SK-BR-3 cells (Cognart et al, 2020). For more information, Ma et al reviewed the studies that employed a microfluidic devices to examine the behavior of cancer cells during metastasis and microcirculation (Ma et al, 2018).…”