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.

中文翻译：

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工程水凝胶揭示了基质力学对食管腺癌的贡献并确定了基质激活的治疗靶点

细胞外基质 (ECM) 硬度的增加与食管腺癌 (EAC) 的进展、转移和治疗耐药有关。然而，潜在的促肿瘤发生途径尚未确定。需要开展更多工作来开发生理相关的体外 3D 培养模型，以更好地概括人类肿瘤微环境，并可用于剖析基质刚度对 EAC 发病机制的影响。在这里，我们描述了一种模块化的肿瘤 ECM 模拟水凝胶平台，具有可调节的机械性能、细胞粘附配体的明确呈现以及蛋白酶依赖性降解，支持患者来源的 EAC 3D 类器官 (EAC PDO) 的稳健体外生长和扩增。水凝胶的机械特性控制 EAC PDO 的形成、生长、增殖和肿瘤相关途径的激活，从而在癌细胞中引发干细胞样特性，正如体外和体内环境所强调的那样。我们还证明，工程水凝胶可作为识别潜在治疗靶点的平台，以破坏 EAC 中促肿瘤基质力学的贡献。总之，这些研究表明，工程化的 PDO 培养平台可用于阐明 EAC 基质介导的潜在机制，并为针对 EAC 中 ECM 硬度的治疗方法的开发提供信息。