Modeling hepatocellular carcinoma and its microenvironment on a chip.

Area of Science:

• Oncology
• Biotechnology
• Drug Discovery

Background:

• Hepatocellular carcinoma (HCC) is a prevalent liver cancer with increasing incidence, linked to advanced liver disease.
• The tumor microenvironment, including cellular stroma and vasculature, critically influences HCC progression and treatment response.
• Developing advanced models is crucial for early-stage drug and target discovery in HCC.

Purpose of the Study:

• To conduct a phenotypic screen using a vascularized hepatocellular carcinoma patient-derived chip (PDChip) model.
• To assess the efficacy of 28 treatment conditions on primary HCC tumors and cell lines within the PDChip model.
• To evaluate drug effects on tumor cell viability, tumor-associated vasculature, and chemokine/cytokine profiles.

Main Methods:

• Utilized approximately 1200 HCC PDChips derived from 8 primary HCC tumors and 2 cell lines.
• Cultured PDChips under perfusion flow and exposed them to various treatment conditions.
• Assessed outcomes including cell viability, vascular bed organization, and changes in chemokine and cytokine release.

Main Results:

• Standard-of-care therapies (sorafenib, lenvatinib) reduced viability but did not affect HCC tumor cells in the PDChip model.
• Atorvastatin decreased PDChip viability but did not alter vascular bed organization.
• Several tested drugs modulated chemokine and cytokine release, with notable effects on IL6 levels.

Conclusions:

• HCC PDChip models provide a robust platform for evaluating drug responses within the tumor and its microenvironment.
• These models are valuable for preclinical research, aiding in disease understanding and the development of novel HCC therapeutics.
• The study highlights limitations of current therapies and the potential of new drug candidates in modulating the HCC microenvironment.