Journal Article

Engineered hydrogel reveals contribution of matrix mechanics to esophageal adenocarcinoma and identifies matrix-activated therapeutic targets

Karaiskos, Spyros, Cruz-Acuña, Ricardo, Burdick, Jason A., Gabre, Joel T., Efe, Gizem, Rustgi, Anil K., Hu, Jianhua, Karakasheva, Tatiana, Kariuki, Secunda W., Sugiura, Kensuke, Loebel, Claudia, Plaster, Eleanor M.

2023

Overview

Increased extracellular matrix (ECM) stiffness has been implicated in esophageal adenocarcinoma (EAC) progression, metastasis, and resistance to therapy. However, the underlying protumorigenic pathways are yet to be defined. Additional work is needed to develop physiologically relevant in vitro 3D culture models that better recapitulate the human tumor microenvironment and can be used to dissect the contributions of matrix stiffness to EAC pathogenesis. Here, we describe a modular, tumor ECM-mimetic hydrogel platform with tunable mechanical properties, defined presentation of cell-adhesive ligands, and protease-dependent degradation that supports robust in vitro growth and expansion of patient-derived EAC 3D organoids (EAC PDOs). Hydrogel mechanical properties control EAC PDO formation, growth, proliferation, and activation of tumor-associated pathways that elicit stem-like properties in the cancer cells, as highlighted through in vitro and in vivo environments. We also demonstrate that the engineered hydrogel serves as a platform for identifying potential therapeutic targets to disrupt the contribution of protumorigenic matrix mechanics in EAC. Together, these studies show that an engineered PDO culture platform can be used to elucidate underlying matrix-mediated mechanisms of EAC and inform the development of therapeutics that target ECM stiffness in EAC.

• Publisher: American Society for Clinical Investigation
• Subject: Adenocarcinoma / Adenocarcinoma - pathology / Adhesives / Analysis / Biological models / Biomedical research / Biomimetics / Biopsy / Cancer / Cell biology / Cell culture / Development and progression / Drug development / Drug therapy / Environmental engineering / Esophageal cancer / Esophageal Neoplasms - genetics / Esophageal Neoplasms - pathology / Esophagus / Ethylenediaminetetraacetic acid / Extracellular matrix / Extracellular Matrix - metabolism / Genomes / Health aspects / Humans / Hydrogels / Ligands / Materials / Mechanical properties / Mechanics / Metastases / Metastasis / Oncology / Organoids / Peptides / Physiological aspects / Proteases / Therapeutic targets / Tumor Microenvironment / Tumors / Verteporfin