Hepatic stellate cells (HSCs) represent a significant component of hepatocellular carcinoma (HCC) microenvironments which play a critical role in tumor progression and drug resistance.Tumor-on-a-chip technology has provided a powerful in vitro platform to investigate the crosstalk between activated Front Suspension HSCs and HCC cells by mimicking physiological architecture with precise spatiotemporal control.Here we developed a tri-cell culture microfluidic chip to evaluate the impact of HSCs on HCC progression.
On-chip analysis revealed activated HSCs contributed to endothelial invasion, HCC drug resistance and natural killer (NK) cell exhaustion.Cytokine array and RNA sequencing analysis were combined to indicate the iron-binding protein Brush Cleaner LIPOCALIN-2 (LCN-2) as a key factor in remodeling tumor microenvironments in the HCC-on-a-chip.LCN-2 targeted therapy demonstrated robust anti-tumor effects both in vitro 3D biomimetic chip and in vivo mouse model, including angiogenesis inhibition, sorafenib sensitivity promotion and NK-cell cytotoxicity enhancement.
Taken together, the microfluidic platform exhibited obvious advantages in mimicking functional characteristics of tumor microenvironments and developing targeted therapies.