PO.TB04.07 · 肿瘤生物学
患者来源胶质母细胞瘤球体所诱导的人血液-肿瘤屏障表型的功能异质性
Functional heterogeneity of the human blood-tumor barrier phenotype induced by patient-derived glioblastoma spheroids
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
胶质母细胞瘤(GBM)有效化疗的根本限制在于血液-肿瘤屏障(BTB)的高度限制性。BTB作为一个稳健的调控界面,严格控制化合物的外排和内流,并极大地限制了治疗药物进入肿瘤微环境。我们假设BTB的功能表型并非静态,而是由肿瘤特征动态调控的。这种观察到的异质性具有临床可操作性:定制药物递送策略以匹配个体肿瘤特征,对于改善预后至关重要。因此,编制一个将BTB转运特征与分子特征相关联的全面数据库,对于指导合理的药物递送设计和优化临床结局是必要的。本研究旨在系统地勾勒BTB转运机制固有的功能异质性,比较由两个不同的患者来源GBM球体(PDS)体外transwell系统所诱导的表型。我们的人类模型利用iPSC来源的脑微血管内皮样细胞(hiPSC-BMECs)与两个PDS样本共培养,以准确模拟复杂的神经血管单元。我们采用多模态功能评估来评价屏障完整性、细胞旁转运、跨细胞通透性和外排特征,以全面表征BTB的被动“渗漏性”和主动“紧密性”。这些发现证实,患者特异性GBM球体诱导出明显异质的BTB功能表型。连接完整性受PDS共培养的调控,异质性响应与GBM分子特征相对应。两者均表现出有限的细胞旁“渗漏性”以及在胞饮和外排机制中失调的主动转运。目前对BTB破坏的临床评估主要依赖于MRI上的钆增强,而这只能检测到粗大的屏障破坏。它无法表征那些显著阻碍药物在肿瘤组织中浓集的微妙、主动且异质的转运机制。我们的体外方法提供了一个必要而精确的转化工具,能够从患者肿瘤样本表征BTB的功能,从而促进在GBM治疗中开发真正个性化且有效的药物递送策略。
查看英文原文 English abstract
The fundamental limitation to effective chemotherapy in Glioblastoma Multiforme (GBM) is the highly restrictive nature of the Blood-Tumor Barrier (BTB). The BTB functions as a robust regulatory interface, tightly controlling the efflux and influx of compounds and greatly restricting therapeutic access to the tumor microenvironment. We hypothesize that the BTB's functional phenotype is not static but is dynamically modulated by tumor characteristics. This observed heterogeneity is clinically actionable: tailoring drug delivery strategies to match individual tumor profiles is essential for improving prognosis. Thus, compiling a comprehensive database correlating BTB transport characteristics with molecular profiles is necessary to inform rational drug delivery design and optimize clinical outcomes. This study was designed to systematically outline the functional heterogeneity inherent in BTB transport mechanisms, comparing phenotypes induced by two separate Patient-Derived GBM Spheroid (PDS) in vitro transwell system. Our human model utilized iPSC-derived Brain Microvascular Endothelial-like Cells (hiPSC-BMECs) co-cultured with the two PDS samples to accurately model the complex neurovascular unit. We utilized a multi-modal functional assessment evaluating barrier integrity, paracellular transport, transcellular permeability, and efflux profile, to comprehensively characterize both the passive "leakiness" and active "tightness" of the BTB. These findings confirm that patient-specific GBM spheroids induce demonstrably heterogeneous BTB functional phenotypes. Junctional integrity is modulated by PDS co-culture, with heterogenous responses corresponding with GBM molecular profile. With limited paracellular “leakiness” and dysregulated active transport seen in both pinocytotic and efflux mechanisms. Current clinical assessment of BTB disruption relies primarily on Gadolinium enhancement on MRI, which only detects gross barrier breakdown. It fails to characterize the subtle, active, and heterogeneous transport mechanisms that significantly impede drug concentration in the tumor mass. Our in vitro approach provides a necessary, precise translational tool capable of characterizing the BTB's function from a patient's tumor sample, facilitating the development of truly personalized and effective drug delivery strategies in GBM therapy.
利益披露 Disclosure
S. Kala, None..
L. M. Markowski, None..
M. E. Katt, None.