PO.TB10.06 · 肿瘤生物学

使用CosMx SMI对胶质母细胞瘤进行空间解析的多组学分析，揭示神经病理学和免疫肿瘤学结构的分子特征

Spatially resolved multiomics profiling of glioblastoma reveals molecular signatures of neuropathology and immuno-oncology architecture using CosMx SMI

编号 809 展板 21 时间 4/19 02:00–05:00 区域 Section 32 主讲 Shanshan He, MD;PhD

分会场 Spatial Protein Profiling and Multi-Modal Mapping of Tumor and Circulating Ecosystems

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作者与单位 Authors & Affiliations

Yi Cui, Claire Williams, Chia-Ying Lee, Chi Phan, Sierra Mckinzie, Shanshan He, Ashley Heck, Kimberley Young, Lidan Wu, John Lyssand, PRAJAN DIVAKAR, Joseph M. Beechem

Bruker Spatial Biology, Seattle, WA

摘要 Abstract

中文摘要

胶质母细胞瘤（GBM）是一种高度异质且侵袭性强的脑肿瘤，治疗成效有限，凸显了对先进方法以解码其复杂分子图景的需求。在此，我们采用CosMx®空间分子成像仪，对来自人类GBM组织块的连续切片进行同细胞空间多组学分析，将全转录组RNA面板（约19,000个基因）与两个高重数蛋白面板（涵盖64种神经病理学或免疫肿瘤学标志物）相整合。这一综合数据集使得能够对肿瘤和瘤周区域的转录组和蛋白质组特征进行关联映射。我们识别出五种GBM肿瘤细胞亚型——星形胶质细胞样、OPC样、间充质样、干细胞样和增殖性细胞——每种都表现出独特的空间定位和转录特征。同步的蛋白分析揭示了区域性富集的磷酸化Tau变体（例如p-Tau S214、S396、S404），其蓄积标志着缺氧和上皮-间充质转化（EMT）活跃的肿瘤微环境。空间回归分析将升高的邻域p-Tau评分与缺氧响应基因（例如HIF1A、VEGFA）和代谢应激通路的协同上调联系起来，揭示了对细胞应激的局部分子响应。免疫肿瘤学蛋白面板的整合突显了空间受限的免疫检查点表达，包括PD-L1、B7-H3和TIM-3，勾勒出不同肿瘤邻域内的免疫逃逸微环境。由不同亚型GBM细胞驱动的肿瘤微环境采用独特的免疫逃逸策略，提示存在微环境特异性的免疫抑制机制。总体而言，本研究展示了空间解析的同细胞多组学以前所未有的分辨率剖析GBM转录组和蛋白质组异质性的能力。研究结果确立了GBM中磷酸化Tau相关应激适应、代谢重塑和免疫调节之间的机制联系。这一可扩展的框架为未来旨在揭示治疗弱点、按微环境特征对肿瘤分层以及识别预测治疗应答的生物标志物的多样本空间肿瘤学研究提供了蓝图。

查看英文原文 English abstract

Glioblastoma (GBM) is a highly heterogeneous and aggressive brain tumor with limited therapeutic success, underscoring the need for advanced approaches to decode its complex molecular landscape. Here, we employed the CosMx® Spatial Molecular Imager to perform same-cell spatial multiomics profiling on serial sections from a human GBM tissue block, integrating the whole-transcriptome RNA panel (~19,000 genes) with two high-plex protein panels encompassing 64 neuropathology or immuno-oncology markers. This comprehensive dataset enables correlative mapping of transcriptomic and proteomic features across tumor and peri-tumoral regions. We identified five GBM tumor cell subtypes - astrocyte-like, OPC-like, mesenchymal-like, stem-like, and proliferating cells - each exhibiting distinct spatial localization and transcriptional signatures. Concurrent protein profiling uncovered regionally enriched phospho-Tau variants (e.g., p-Tau S214, S396, S404), whose accumulation marked hypoxic and epithelial-mesenchymal transition (EMT) active tumor microenvironments. Spatial regression analyses linked elevated neighborhood p-Tau scores to coordinated upregulation of hypoxia-responsive genes (e.g., HIF1A, VEGFA) and metabolic stress pathways, revealing a localized molecular response to cellular stress. Integration of the immuno-oncology protein panel highlighted spatially restricted immune checkpoint expression, including PD-L1, B7-H3, and TIM-3, delineating immune-evasive niches within distinct tumor neighborhoods. Tumor niches driven by divergent subtype GBM cells adopted unique immune evasion strategies, suggesting microenvironment-specific mechanisms of immune suppression. Overall, this study demonstrates the power of spatially resolved, same-cell multiomics to dissect GBM's transcriptional and proteomic heterogeneity at unprecedented resolution. The findings establish a mechanistic link between phospho-Tau-associated stress adaptation, metabolic remodeling, and immune modulation in GBM. This scalable framework offers a blueprint for future multi-sample spatial oncology studies aimed at uncovering therapeutic vulnerabilities, stratifying tumors by microenvironmental features, and identifying biomarkers predictive of treatment response.

利益披露 Disclosure

Y. Cui, None.. C. Williams, None.. C. Lee, None.. C. Phan, None.. S. Mckinzie, None.. S. He, None.. A. Heck, None.. K. Young, None.. L. Wu, None.. J. Lyssand, None.. P. Divakar, None.. J. M. Beechem, None.

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