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Abstract Dysregulation of the extracellular matrix (ECM) properties disturbs tissue homeostasis and contributes to pathological conditions, such as cancer. Recent studies have demonstrated that ECM stiffening is associated with metaplasia-dysplasia-adenocarcinoma sequence in the esophagus. This underscores a compelling need to develop a physiologically-relevant 3D culture model to enable the study of the independent contribution of matrix stiffness to the initiation and progression of esophageal adenocarcinoma (EAC). Such a model will then serve as a platform for pre-clinical drug screening in the context of matrix properties. In this context, we have engineered a hyaluronic acid-based 3D hydrogel platform that supports the growth and differentiation of patient-derived Barrett’s esophagus (BE) organoids, a precursor to EAC, as well as patient-derived EAC organoids. The engineered biomaterial 3D platform allows control over matrix stiffness to better recapitulate the mechanically dynamic esophageal cancer microenvironment and help identify therapeutic targets in EAC. Our data demonstrates that BE and EAC organoid density, growth and proliferation can be controlled by matrix stiffness. RNA sequencing data show that increased matrix stiffness promotes changes in the transcriptional profiles of BE and EAC organoids, revealing enrichment of pathways associated with tumorigenesis and disease progression. Furthermore, we demonstrate through molecular and functional assays that increased matrix stiffness endows stem-like properties to the EAC organoids via Yap-Sox9 mechano-activation. Finally, targeted therapy studies in our in vitro and in vivo engineered environments revealed that Yap inhibition regressed the effects of increased matrix stiffness in EAC organoids. In summary, our data suggest that matrix mechanics have a significant role in activation of EAC-associated signaling pathways in patient-derived BE and EAC organoids. We also demonstrate that the engineered hydrogel serves as a platform to identify potential therapeutic targets to disrupt the contribution of pro-tumorigenic matrix mechanics in EAC. Together, these studies establish an engineered patient-derived organoid culture platform that can be used to elucidate underlying matrix-mediated mechanisms of the metaplasia-dysplasia-adenocarcinoma sequence and inform the development of novel therapeutics that target ECM stiffness in EAC. FUNDING SOURCES: NCI P01CA098101, U54 CA163004 and NIDDK K01 DK133620. Citation Format: Ricardo Cruz-Acuna, Secunda W. Kariuki, Kensuke Sugiura, Spyros Karaiskos, Eleanor M. Plaster, Claudia Loebel, Gizem Efe, Tatiana Karakasheva, Joel T. Gabre, Jianhua Hu, Jason A. Burdick, Anil K. Rustgi. Engineered hydrogel elucidates contributions of matrix mechanics to pathobiology of adenocarcinoma and identify matrix-activated therapeutic targets abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 4268.
Cruz‐Acuña et al. (Fri,) studied this question.