PO.TB01.01 · 肿瘤生物学
Galectin-1作为胶质母细胞瘤中血管生成和代谢重编程的核心调控因子
Galectin-1 as a central regulator of angiogenesis and metabolic reprogramming in glioblastoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
胶质母细胞瘤(GB)是中枢神经系统中最具侵袭性的肿瘤,以快速生长和对现有疗法的显著耐药为特征。其生物学特性由深刻的瘤间和瘤内异质性、高度免疫抑制的微环境,以及对代谢和血管适应的强烈依赖所塑造,这些适应使肿瘤细胞得以在缺氧和营养匮乏的条件下茁壮生长。富含胶质瘤干样细胞(GSCs)的亚群在这些适应中发挥核心作用,通过灵活的代谢和血管生成程序维持肿瘤扩张。Galectin-1(GAL1)是一种在肿瘤微环境中具有多重作用的聚糖结合凝集素,在胶质瘤中显著升高。这促使我们探究GAL1是否可作为GB中代谢和血管生成的共同调控因子。我们建立了患者来源的GSC细胞系(G02、G03、G08、G09),这一模型保留了该疾病典型的临床异质性。RNA-seq和功能实验揭示了细胞系之间的明显差异。G02表现出内皮样特征并促进内皮细胞迁移,而G03富含血管生成相关通路并在体外形成稳固的管样结构,与较高的VEGF分泌相一致(p<0.01)。来自相应患者(G02和G03)的活检标本再现了这一生物学特征,显示出广泛的微血管增生区域。使用抗体或siRNA抑制GAL1主要在G03中降低了管形成,提示并非所有血管生成谱都可能依赖GAL1。代谢分析进一步支持这一观点。Seahorse分析显示,G02和G03对GAL1耗竭的反应是转向相反的代谢程序,补充实验(TMRE、MitoSOX)揭示G02具有高线粒体活性(FC=2),而G09表现出OXPHOS受损(FC=0.5)。综上,我们的数据表明分泌型和细胞内GAL1均参与维持GB生长的代谢和血管生成适应。这些结果强调GSCs依赖于不同但相互协调的策略以获取资源,并将GAL1定位为这些过程的核心调控因子。界定决定对GAL1抑制敏感性的细胞和功能特征,可能有助于指导为胶质母细胞瘤开发更精准的抗血管生成或代谢疗法。
查看英文原文 English abstract
Glioblastoma (GB) is the most aggressive tumor of the central nervous system characterized by rapid growth and remarkable resistance to current therapies. Its biology is shaped by profound inter- and intra-tumoral heterogeneity, a highly immunosuppressive microenvironment, and a strong dependence on metabolic and vascular adaptations that allow tumor cells to thrive under hypoxic and nutrient-poor conditions. A subpopulation enriched in glioma stem-like cells (GSCs) plays a central role in these adaptations, sustaining tumor expansion through flexible metabolic and angiogenic programs. Galectin-1 (GAL1), a glycan-binding lectin with multiple roles in the tumor microenvironment, is considerably elevated in gliomas. This led us to investigate whether GAL1 could act as a common regulator of both metabolism and angiogenesis in GB. We established patient-derived GSC lines (G02, G03, G08, G09), a model that preserves the clinical heterogeneity typical of this disease. RNA-seq and functional assays revealed clear differences among cell lines. G02 showed an endothelial-like signature and promoted endothelial cell migration, while G03 was enriched in angiogenesis-related pathways and formed robust tube-like structures in vitro, in line with higher VEGF secretion (p<0.01). Biopsies from the corresponding patients (G02 and G03) recapitulated this biology, displaying broad areas of microvascular proliferation. Inhibition of GAL1 with antibodies or siRNA reduced tube formation mainly in G03, suggesting that not all angiogenic profiles are likely dependent on GAL1. Metabolic analysis further supported this idea. Seahorse analysis showed that G02 and G03 respond to GAL1 depletion by shifting toward opposite metabolic programs, and complementary assays (TMRE, MitoSOX) revealed high mitochondrial activity in G02 (FC=2), while G09 displayed impaired OXPHOS (FC=0.5). Together, our data indicate that both secreted and intracellular GAL1 contribute to the metabolic and angiogenic adaptations that sustain GB growth. These results emphasize that GSCs rely on distinct yet coordinated strategies to obtain resources, and position GAL1 as a central regulator of these processes. Defining the cellular and functional profiles that determine sensitivity to GAL1 inhibition may help guide the development of more precise anti-angiogenic or metabolic therapies for glioblastoma.
利益披露 Disclosure
L. B. Ripari, None..
J. P. Merlo, None..
M. B. Vera, None..
O. Morris-Hanon, None..
M. B. Mezmezian, None..
M. Hermida, None..
G. E. Sevlever, None..
D. O. Croci, None..
G. A. Videla-Richardson*, None..
G. A. Rabinovich*, None.