Abstract 2704: 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. 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 regulates tumor initiation, progression, metastasis, and therapy response. Current in vitro systems often fail to replicate the HCC complex microenvironment, including vascular structures, hindering accurate efficacy evaluation and limiting the translational value of preclinical studies. This study aimed to address these gaps by developing a scalable, vascularized 3D HCC model using the OrganoPlate Graft platform to enable detailed analyses of drug responses, bridging a critical gap in anticancer drug discovery Here we report a phenotypic drug screen on a HCC patient-derived comprehensive Organ-on-a-Chip setup. The vascularized patient-derived HCC models include relevant cellular players of the HCC microenvironment. These co-cultures are highly suitable for studying specific cell types as well as patient-specific responses in medium- to high- throughput fashion. We assessed the effect of 28 treatment conditions, including standard of care (SoC), single, and combination treatments with compounds targeting different molecular programs. Approximately 960 HCC patient derived cultures were grown under perfusion flow in microfluidic chips, exposed to treatments, and subsequently assessed for viability, chemokine and cytokine changes, and vascular bed responses. The screen showed known therapeutics sorafenib and lenvatinib to reduce culture viability and induce significant alterations in vascular bed organization. Compound 1 reduced viability without affecting vascular structures. All three compounds also affected chemokine and cytokine profiles. Additionally, several compounds including Compound 25, Compound 5 and Compound15 lowered IL6 in culture supernatant, whereas Compound 6 elevated IL6 levels. These findings highlight the utility of the organ-on-a-chip 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 holds significant potential for enabling safer and more effective drug development, offering scalability and ease of use for industrial applications. By addressing critical limitations of conventional in vitro models, this approach facilitates a more accurate understanding of HCC biology and supports the translation of novel anticancer therapies to clinical practice. Citation Format: Orsola Mocellin, Abbie Robinson, Aleksandra Olczyk, Stephane Treillard, Thomas Olivier, Chee P Ng, Jeroen Heijmans, Gilles van Tienderen, Monique Verstegen, Flavio Bonanini, Sebastian J. Trietsch, Dorota Kurek, Henriette Lanz, Jos Joore, Paul Vulto, Karla S. 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 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2704.