胶质瘤血管系统全脑全景图的构建揭示了肿瘤的异质性和血脑屏障的破坏

IF 12.5 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances Pub Date : 2025-07-23 DOI:10.1126/sciadv.adw8330

Chenxi Huang, Xiaohong Xin, Xiaoxu Hao, Shilin Zhou, Zongneng Xie, Lijuan He, Xiaoliang Li, Yu Zhang, Hongyu Sun, Jiwen Zhang, Xiaochuan Zhang, Xianzhen Yin

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引用次数: 0

摘要

血管诱导的肿瘤组织异质性阻碍了可预测的药物分布，并为优化基于纳米颗粒（NP）的药物递送提出了显着挑战。然而，整个大脑的中观尺度肿瘤异质性特征仍然很差。为了解决这一问题，我们将显微光学断层扫描（MOST）与高精度三维（3D）重建分析相结合，在亚微米分辨率下绘制整个小鼠大脑的原位胶质瘤病理特征。我们的研究结果揭示了胶质瘤侵袭性、脉管系统和代偿性血管生成的显著异质性，同时精确地描绘了NP在整个肿瘤中的分布。值得注意的是，早期胶质瘤在胶质瘤植入后的4天内，沿着大脑主动脉向上游迁移了680微米。在胶质瘤进展过程中，血脑屏障通透性逐渐增加，使NP能够通过大直径血管而不是局限于毛细血管渗透。这项工作建立了一个多尺度、高分辨率的神经胶质瘤异质性和NP分布的3D图谱，并将介观结构复杂性与功能性药物传递障碍联系起来，推进了提高异质性脑肿瘤治疗精度的策略。

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Construction of a whole-brain panorama for glioma vasculature reveals tumor heterogeneity and blood-brain barrier disruption

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Construction of a whole-brain panorama for glioma vasculature reveals tumor heterogeneity and blood-brain barrier disruption

Vasculature-induced tumor tissue heterogeneity impedes predicable drug distribution and presents notable challenges for optimizing nanoparticle (NP)–based drug delivery. However, mesoscopic-scale tumor heterogeneity across entire brain remains poorly characterized. To address this, we integrated micro-optical sectioning tomography (MOST) with high-precision three-dimensional (3D) reconstruction analysis to map pathological features of orthotopic glioma at submicron resolution across whole mice brain. Our findings uncovered significant heterogeneity in glioma invasiveness, vasculature, and compensatory angiogenesis while precisely delineating NP distribution throughout the tumor. Notably, early-stage glioma co-opted and migrated 680-micrometer upstream along the main cerebral artery within 4 days after glioma implantation. Blood-brain barrier permeability gradually increased during glioma progression, enabling NP penetrated via large-diameter vessels instead being restricted to capillaries. This work establishes a multiscale, high-resolution, 3D atlas of glioma heterogeneity and NP distribution, and bridges mesoscopic structural complexity to functional drug delivery barriers, advancing strategies to enhance oncotherapy precision in heterogeneous brain tumors.

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来源期刊

Science Advances 综合性期刊-综合性期刊

CiteScore

21.40

自引率

1.50%

发文量

1937

审稿时长

29 weeks

期刊介绍： Science Advances, an open-access journal by AAAS, publishes impactful research in diverse scientific areas. It aims for fair, fast, and expert peer review, providing freely accessible research to readers. Led by distinguished scientists, the journal supports AAAS's mission by extending Science magazine's capacity to identify and promote significant advances. Evolving digital publishing technologies play a crucial role in advancing AAAS's global mission for science communication and benefitting humankind.