Treillard, S. | Search bioRxiv

bioRxiv2025

Modeling Hepatocellular Carcinoma and its microenvironment on a chip

Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Its incidence is increasing and is closely related to advanced liver disease. Interactions in the HCC microenvironment between tumor cells and the associated stroma actively regulate tumor initiation, progression, metastasis, and therapy response. Effective drug development increasingly requires advanced models that can be utilized in the earliest stages of compound and target discovery. Here we report a phenotypic screen on an advanced HCC patient-derived chip (PDChip) model. The vascularized HCC PDChip models include relevant cellular players of the HCC microenvironment. We assessed the effect of 28 treatment conditions on a panel of 8 primary HCC tumors and 2 cell lines. Approximately 1200 HCC PDchips were grown under perfusion flow, exposed to treatments, and subsequently assessed for viability, tumor-associated vasculature responses and chemokine and cytokine changes. Although the SoC therapeutics sorafenib and lenvatinib reduced culture viability and produced profound changes in the organization of the vascular beds, they did not affect the tumor cell population in these cultures. Atorvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, reduced tumor viability but did not affect vascular bed organization. Sorafenib, lenvatinib and atorvastatin also affected chemokine and cytokine release. Tocilizumab, galunisertib, and vactosertib decreased the level of IL6, a relevant prognostic marker for HCC, while IL6 was increased by halofuginone. In conclusion, HCC PDChip models enabled a detailed evaluation of drug-induced responses in the tumor and associated microenvironment, highlighting their importance in preclinical research for understanding diseases and developing new drugs.

bioengineering↗

bioRxiv2024

A microvascularized in vitro liver model for disease modeling and drug discovery

Drug discovery for complex liver diseases faces alarming attrition rates. The lack of non-clinical models that recapitulate key aspects of liver (patho)-physiology is likely contributing to the inefficiency of developing effective treatments. Of particular notice is the common omission of an organized microvascular component despite its importance in maintaining liver function and its involvement in the development of several pathologies. Increasing the complexity of in vitro models is usually associated with a lack of scalability and robustness which hinders their implementation in drug development pipelines. Here, we describe a comprehensive liver MPS model comprising stellates, liver-derived endothelial cells and hepatocytes conceived within a scalable and automated platform. We show that endothelial cells self-organize in a microvascular network when co-cultured with stellates in a hydrogel. In a tri-culture, hepatocytes polarize accordingly, with a basolateral side facing blood vessels and an apical side facing bile-canaliculi-like structures. Stellates interact and surround the hollow microvessels. Steatosis was induced by exogenous administration of fatty acids which could be prevented by co-administration of firsocostat. Administration of TGF-{beta} resulted in an activated stellate cells phenotype which could be prevented by the co-administration of SB-431542. The model was implemented on a microtiter plate format comprising 64 chips which enabled the development of a fully automated, multiplexed fibrosis assay with a robust Z factor suitable for high-throughput applications.

bioengineering↗