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胶质母细胞瘤中缺氧巨噬细胞的鉴定具有血管正常化的治疗潜力
作者:小柯机器人 发布时间:2024/4/20 16:13:05

第三军医大学时雨等研究人员合作发现,胶质母细胞瘤中缺氧巨噬细胞的鉴定具有血管正常化的治疗潜力。该项研究成果于2024年4月18日在线发表在《癌细胞》杂志上。

利用单细胞转录组学,研究人员绘制了51例异柠檬酸脱氢酶(IDH)野生型胶质母细胞瘤或IDH突变型胶质瘤患者的,单核细胞来源肿瘤相关巨噬细胞(Mo-TAM)空间分辨率转录图谱。研究人员发现了一个Mo-TAM亚群的特征,该亚群定位在坏死微环境周围,并受缺氧微环境线索的影响而获得缺氧反应特征。缺氧-TAM通过激活肾上腺髓质素旁分泌信号,破坏内皮粘连接头的稳定性,从而刺激新血管的高渗透性,阻碍胶质母细胞瘤异种移植物的药物输送。
 
因此,通过基因消融或药物阻断低氧-TAM产生的肾上腺髓质素,可恢复血管完整性,并提高抗肿瘤药物达拉非尼的瘤内浓度,以实现综合治疗效果。低氧-TAM或肾上腺髓质素表达比例的增加,可预测肿瘤血管的高渗透性和胶质母细胞瘤的不良预后。这些研究结果突显了弥漫性胶质瘤中Mo-TAM的多样性,和以空间微环境为中心的Mo-TAM重编程,并预示着针对缺氧-TAM的潜在疗法可使肿瘤血管正常化。

研究人员表示,Mo-TAM以显著的异质性密集浸润弥漫性胶质瘤。

附:英文原文

Title: Identification of hypoxic macrophages in glioblastoma with therapeutic potential for vasculature normalization

Author: Wenying Wang, Tianran Li, Yue Cheng, Fei Li, Shuhong Qi, Min Mao, Jingjing Wu, Qing Liu, Xiaoning Zhang, Xuegang Li, Lu Zhang, Haoyue Qi, Lan Yang, Kaidi Yang, Zhicheng He, Shuaishuai Ding, Zhongyi Qin, Ying Yang, Xi Yang, Chunhua Luo, Ying Guo, Chao Wang, Xindong Liu, Lei Zhou, Yuqi Liu, Weikai Kong, Jingya Miao, Shuanghui Ye, Min Luo, Lele An, Lujing Wang, Linrong Che, Qin Niu, Qinghua Ma, Xia Zhang, Zhihong Zhang, Rong Hu, Hua Feng, Yi-Fang Ping, Xiu-Wu Bian, Yu Shi

Issue&Volume: 2024-04-18

Abstract: Monocyte-derived tumor-associated macrophages (Mo-TAMs) intensively infiltrate diffusegliomas with remarkable heterogeneity. Using single-cell transcriptomics, we charta spatially resolved transcriptional landscape of Mo-TAMs across 51 patients withisocitrate dehydrogenase (IDH)-wild-type glioblastomas or IDH-mutant gliomas. We characterizea Mo-TAM subset that is localized to the peri-necrotic niche and skewed by hypoxicniche cues to acquire a hypoxia response signature. Hypoxia-TAM destabilizes endothelialadherens junctions by activating adrenomedullin paracrine signaling, thereby stimulatinga hyperpermeable neovasculature that hampers drug delivery in glioblastoma xenografts.Accordingly, genetic ablation or pharmacological blockade of adrenomedullin producedby Hypoxia-TAM restores vascular integrity, improves intratumoral concentration ofthe anti-tumor agent dabrafenib, and achieves combinatorial therapeutic benefits.Increased proportion of Hypoxia-TAM or adrenomedullin expression is predictive oftumor vessel hyperpermeability and a worse prognosis of glioblastoma. Our findings highlight Mo-TAM diversity and spatial niche-steered Mo-TAM reprogramming in diffusegliomas and indicate potential therapeutics targeting Hypoxia-TAM to normalize tumor vasculature.

DOI: 10.1016/j.ccell.2024.03.013

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(24)00119-3

期刊信息

Cancer Cell:《癌细胞》,创刊于2002年。隶属于细胞出版社,最新IF:38.585
官方网址:https://www.cell.com/cancer-cell/home
投稿链接:https://www.editorialmanager.com/cancer-cell/default.aspx