000168661 001__ 168661
000168661 005__ 20260219141450.0
000168661 0247_ $$2doi$$a10.1016/j.actbio.2026.01.013
000168661 0248_ $$2sideral$$a148061
000168661 037__ $$aART-2026-148061
000168661 041__ $$aeng
000168661 100__ $$aMartín-Contreras, Alejandro$$uUniversidad de Zaragoza
000168661 245__ $$aLocal mechanobiological disruption in solid tumor-driven vascular permeability: A competition between mechanical vs chemical stimuli
000168661 260__ $$c2026
000168661 5060_ $$aAccess copy available to the general public$$fUnrestricted
000168661 5203_ $$aThe tumor microenvironment imposes complex biochemical and biomechanical constraints on microvasculature, contributing to aberrant tumor blood vessels, characterized by abnormal endothelial proliferation, disrupted cell-to-cell junctions and increased permeability. While vascular normalization strategies have traditionally focused on biochemical modulation, the role of mechanical forces in endothelial dysfunction remains unclear. Here, we used a microfluidic platform to dissect the mechanobiological impact of two distinct solid tumor models —pancreatic ductal adenocarcinoma (PANC-1) and lung adenocarcinoma (A549)—on three-dimensional embedded endothelial vessels. Our findings reveal that PANC-1 spheroids exert significant mechanical forces, expanding vessel diameter and disrupting endothelial barrier integrity via cellular contractility. Conversely, A549 spheroids contribute to vascular destabilization through biochemical modulation, primarily via extracellular matrix degradation and inflammatory secretomes, leading to an altered and heterogeneous endothelial permeability. Proteomic analysis of both tumor cell lines highlights distinct pathways involved in endothelial remodeling: cytoskeletal alterations and consequent stresses in pancreatic ductal adenocarcinoma, while extracellular matrix remodeling and pro-inflammatory microenvironment are found in lung adenocarcinoma. These insights underscore the necessity of tumor-specific vascular normalization strategies, combining mechanobiological and biochemical approaches to restore endothelial barrier function. Our locally controlled microfluidic approach provides a versatile platform for evaluating innovative therapeutic strategies targeting tumor-specific vasculature. Statement of significance This study highlights the often-overlooked role of tumor-derived mechanical forces in vascular dysfunction. Within the tumor microenvironment, different tumor types disrupt the endothelial barrier through distinct, tumor-specific mechanisms, leading to varied patterns of vessel instability. Using confocal microscopy, we achieved spatially resolved analysis of local endothelial barrier damage, distinguishing focal from diffuse permeability changes. A 3D microfluidic platform was developed to replicate tumor endothelium interactions, combining live imaging, morphometric and biochemical assays, and proteomic profiling. This integrative model offers a versatile tool for evaluating drug responses under controlled mechanochemical conditions, supporting the development of personalized vascular-targeted therapies.
000168661 536__ $$9info:eu-repo/grantAgreement/EC/H2020/101018587/EU/Individual and Collective Migration of the Immune Cellular System/ICoMICS$$9This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No H2020 101018587-ICoMICS$$9info:eu-repo/grantAgreement/ES/MINECO/PID2024-155426OB-I00
000168661 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttps://creativecommons.org/licenses/by/4.0/deed.es
000168661 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000168661 700__ $$aSarasquete-Martínez, María$$uUniversidad de Zaragoza
000168661 700__ $$0(orcid)0000-0002-9864-7683$$aGarcía-Aznar, José Manuel$$uUniversidad de Zaragoza
000168661 700__ $$aGonzález-Loyola, Alejandra
000168661 700__ $$0(orcid)0000-0002-1878-8997$$aGómez-Benito, María José$$uUniversidad de Zaragoza
000168661 7102_ $$15008$$2800$$aUniversidad de Zaragoza$$bDpto. Ingeniería Electrón.Com.$$cÁrea Teoría Señal y Comunicac.
000168661 7102_ $$15004$$2605$$aUniversidad de Zaragoza$$bDpto. Ingeniería Mecánica$$cÁrea Mec.Med.Cont. y Teor.Est.
000168661 773__ $$g(2026), [15 pp.]$$pActa Biomater.$$tACTA BIOMATERIALIA$$x1742-7061
000168661 8564_ $$s11642359$$uhttps://zaguan.unizar.es/record/168661/files/texto_completo.pdf$$yVersión publicada
000168661 8564_ $$s2346185$$uhttps://zaguan.unizar.es/record/168661/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000168661 909CO $$ooai:zaguan.unizar.es:168661$$particulos$$pdriver
000168661 951__ $$a2026-02-19-14:14:15
000168661 980__ $$aARTICLE