Engineered hydrogel reveals contribution of matrix mechanics to esophageal adenocarcinoma 3D organoids and identify matrix-activated therapeutic targets

Abstract

Increased extracellular matrix (ECM) stiffness has been implicated in esophageal adenocarcinoma (EAC) progression, metastasis, and resistance to therapy. However, the underlying pro-tumorigenic 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 to identify potential therapeutic targets to disrupt the contribution of pro-tumorigenic increased matrix mechanics in EAC. Together, these studies show that an engineered PDO culture platform can be used to inform the development of therapeutics that target ECM stiffness in EAC.

Organoids in gastrointestinal diseases: from bench to clinic

“…180,181 They also serve as a means to continuously identify new targets and design targeted therapy strategies. [182][183][184][185] Organoids models also facilitate the exploration of alternative treatment approaches for challenging drug targets. For instance, though certain therapeutic strategies targeting the WNT pathway often lead to adverse effects on normal crypt development, innovative approaches focusing on terminal differentiation have shown promise in resolving these issues.…”