Abstract 3838: Engineered hydrogel elucidates contributions of matrix mechanics to esophageal adenocarcinoma and identify matrix-activated therapeutic targets

Abstract

Abstract INTRODUCTION: 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. However, these studies are limited by the lack of 3D intercellular interactions, underscoring the need for physiologically relevant 3D culture models, such as patient-derived organoids (PDOs), 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, PDOs have become an attractive pre-clinical in vitro model to study cancer biology and evaluate response to therapeutics. METHODS: 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. RESULTS: Our preliminary data have demonstrated that BE and EAC organoid density, size and proliferation can be controlled by synthetic ECM biomechanical properties. Furthermore, our data show that increased matrix stiffness promotes changes in the transcriptional profiles of EAC organoids, as observed via Principal Component Analysis, and gene set enrichment analysis of upregulated genes reveals enrichment of anti-apoptotic pathways. This suggests that the synthetic ECM facilitates activation of mechanotransduction pathways in EAC organoids and that matrix mechanics have a significant role in activation of canonical anti-apoptotic signaling pathways. Ongoing studies involve identifying matrix stiffness-activated therapeutic targets via small molecule inhibition of upregulated genes that are considered prospective biomarkers in GI cancer. SUMMARY: 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. 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 matrix biomechanics.FUNDING: NCI P01-CA098101, U54 CA-163004 and Charles H. Revson Senior Fellowships in Biomedical Science. Citation Format: Ricardo Cruz-Acuña, Secunda W. Kariuki, Claudia Loebel, Tatiana Karakasheva, Joel T. Gabre, 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 American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3838.