Abstract 733: Targeting HCC tumor microenvironment interactions using an advanced HCC patient-derived on-chip model.

Abstract Hepatocellular carcinoma (HCC) is the most common type of liver cancer, with rising incidence closely linked to advanced liver disease. Interactions within the HCC tumor microenvironment (TME)—between tumor cells and associated stroma—actively regulate tumor initiation, progression, metastasis, and therapy response. Current in vitro systems often fail to replicate this complex microenvironment, including vascular structures, limiting accurate efficacy evaluation and the translational value of preclinical studies. To address these gaps, we developed a scalable, vascularized 3D HCC patient-derived Organ-on-a-Chip (PDChip) model using the OrganoPlate Graft platform. This advanced system incorporates relevant cellular players of the HCC microenvironment and enables medium- to high-throughput phenotypic drug screening. Approximately 1,200 patient-derived cultures from 8 primary HCC tumors and 2 cell lines were grown under perfusion flow, exposed to 28 treatment conditions—including standard of care (SoC), single agents, and combinations—and assessed for viability, vascular bed responses, and chemokine/cytokine changes. The screen revealed that SoC drugs sorafenib and lenvatinib reduced culture viability and induced profound changes in vascular bed organization, while atorvastatin decreased viability without affecting vascular structures. All three compounds also altered chemokine and cytokine profiles. Tocilizumab, galunisertib, and vactosertib lowered IL6 levels, whereas halofuginone increased IL6. These findings highlight the utility of the PDChip model in visualizing drug-induced responses at both molecular and morphological levels, providing detailed insights into drug effects on specific cellular compartments within the HCC TME. This platform 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. Citation Format: Orsola Mocellin, Stephane Treillard, Abbie Robinson, Aleksandra Olczyk, Thomas Olivier, Chee P. Ng, Arthur Stok, Giles van Tienderen, Monique Verstegen, Jeroen Heijmans, Dorota Kurek, Sebastian J. Trietsch, Henriëtte Lanz, Paul Vulto, Jos Joore, Karla Queiroz. Targeting HCC tumor microenvironment interactions using an advanced HCC patient-derived on-chip model abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 733.