PhD Dissertation: Gülin Baran, DECIPHERING GLIOBLASTOMA–BLOOD–BRAIN BARRIER INTERACTIONS THROUGH HUMANIZED IN VITRO SYSTEMS: FROM MECHANISTIC UNDERSTANDING TO THERAPEUTIC INSIGHT,

DECIPHERING GLIOBLASTOMA–BLOOD–BRAIN BARRIER INTERACTIONS THROUGH HUMANIZED IN VITRO SYSTEMS: FROM MECHANISTIC UNDERSTANDING TO THERAPEUTIC INSIGHT

Gülin Baran
Molecular Biology, Genetics and Bioengineering, PhD Dissertation, 2025

Thesis Jury

Asst. Prof. Nur Mustafaoglu.(Dissertation Supervisor)

Asst. Prof. Sibel Çetinel
Prof. Bahattin Koç

Asst. Zeynep Tokcaer-Keskin

Asst. Prof. Ece Öztürk

Date & Time: December 19th, 2025 – 2:00 PM

Place: FASS 1010

Keywords : glioblastoma biology, blood-brain barrrier, iPSC, microfluidic device, drug

Abstract

Glioblastoma (GBM), an invasive tumor of the central nervous system, exhibits nearly all classical hallmarks of cancer. Despite decades of research, its biology remains incompletely understood, particularly regarding its rare metastatic behavior, tumor–microenvironment crosstalk, and strong resistance to drug delivery imposed by the blood–brain barrier (BBB) and blood–tumor barrier. To address these gaps, this dissertation investigates GBM within the context of its limited metastatic potential, dynamic microenvironmental interactions, and targeted therapy approaches. We developed physiologically relevant, fully human cell–based in vitro GBM models integrated with BBB compartments composed of human induced pluripotent stem cell–derived brain microvascular endothelial cells (iBMECs), astrocytes, pericytes, and GBM cells within custom-made microfluidic devices. Our findings demonstrate that astrocyte-derived secretomes significantly enhance GBM invasiveness, while GBM- and astrocyte/GBM-conditioned media reshape the proteomic profile of iBMECs, inducing partial and reversible endothelial-to-mesenchymal transition without compromising barrier integrity, suggesting a mechanism contributing to GBM’s rare metastatic nature. We further established 3D healthy BBB-on-a-chip and GBM-BBB-on-a-chip platforms to investigate GBM-derived extracellular vesicles, revealing distinct particle signatures in healthy versus diseased conditions. These models also enabled the evaluation of nanoparticle-based drug shuttling systems. Finally, we engineered surface-modified rice husk-derived mesoporous silica nanoparticles functionalized with amine, carboxyl, or polyethylene glycol groups to assess their drug delivery efficiency across the human BBB under both healthy and GBM conditions. Overall, this work demonstrates that physiologically relevant, humanized GBM-BBB-on-a-chip models are powerful platforms for dissecting GBM biology and evaluating nanoparticle-based therapeutic strategies, supporting their application in targeted and personalized medicine.