Abstract P114: Engineered hydrogel elucidates contributions of matrix mechanics to esophageal adenocarcinoma and identify matrix-activated therapeutic targets

Abstract

Abstract Changes in the tumor microenvironment arbitrated by a stiffened ECM are associated with tumor aggression and enable increased propensity towards metastasis. For instance, in vitro (2D) studies have implicated ECM properties in EAC progression, suggesting their exploitation for esophageal therapy following surgical resection. However, these studies are limited by the lack of 3D intercellular interactions, underscoring the need for physiologically relevant 3D culture models (e.g., organoids) that better recapitulate human cancer and its microenvironment to elucidate underlying mechanisms. Engineered hydrogels are an evolving and important component of 3D organoid culture systems, especially to introduce tunable physicochemical matrix signals that have been investigated in tumor progression and metastasis. Furthermore, patient-derived tumor organoids have become an attractive pre-clinical in vitro model to study cancer biology and evaluate response to therapeutics. Therefore, we have engineered a visible light-mediated hydrogel platform that supports the development of patient-derived Barrett’s esophagus (BE) organoids, a precursor to esophageal adenocarcinoma (EAC), as well as EAC organoids. This synthetic biomaterial platform allows control over hydrogel stiffness to better recapitulate the mechanically dynamic esophageal cancer microenvironment, and may help identify therapeutic targets in EAC organoids. Our preliminary data have demonstrated that BE and EAC organoid density, size and proliferation can be controlled by synthetic ECM biomechanical properties, demonstrating the significance of understanding the independent contributions of ECM properties to EAC development, which is inherently limited in biologically-derived materials (e.g. MatrigelTM). Furthermore, our data show that increased hydrogel stiffness promotes increased expression of mutant TP53, and increased SOX9 expression as a result of YAP1 activation, suggesting that matrix mechanics have a significant role in conferring stem-like properties to EAC organoids via activation of canonical oncogenic signaling pathways. Ongoing studies involve identifying matrix-activated therapeutic targets via small-molecule inhibition of TP53 and YAP1, as a function of matrix stiffening, and identifying differentially expressed genes using high-throughput transcriptome sequencing between stiffened hydrogel-encapsulated EAC organoid conditions. Our work is significant because it establishes a biomaterial platform that overcomes the limitations of current 3D organoid culture methods to elucidate the role of the tumor microenvironment in EAC tumorigenesis and to identify disease-relevant therapeutic targets. Successful completion of this work will also provide an opportunity to further establish the engineered biomaterial as a platform to potentially elucidate the mechanisms of, and therapy targets for, other human adenocarcinomas in the context of changes in the mechanics of tumor microenvironment. Citation Format: Ricardo Cruz-Acuña, Claudia Loebel, Jason A. Burdick, Anil K. Rustgi. Engineered hydrogel elucidates contributions of matrix mechanics to esophageal adenocarcinoma and identify matrix-activated therapeutic targets [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P114.