Patel Kunal S, Tessema Kaleab K, Kawaguchi Riki, Dudley Lindsey, Alvarado Alvaro G, Muthukrishnan Sree Deepthi, Perryman Travis, Hagiwara Akifumi, Swarup Vivek, Liau Linda M, Wang Anthony C, Yong William, Geschwind Daniel H, Nakano Ichiro, Goldman Steven A, Everson Richard G, Ellingson Benjamin M, Kornblum Harley I
Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
The Intellectual and Developmental Disabilities Research Center and Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
Neurooncol Adv. 2024 Jan 25;6(1):vdae005. doi: 10.1093/noajnl/vdae005. eCollection 2024 Jan-Dec.
Non-enhancing (NE) infiltrating tumor cells beyond the contrast-enhancing (CE) bulk of tumor are potential propagators of recurrence after gross total resection of high-grade glioma.
We leveraged single-nucleus RNA sequencing on 15 specimens from recurrent high-grade gliomas ( = 5) to compare prospectively identified biopsy specimens acquired from CE and NE regions. Additionally, 24 CE and 22 NE biopsies had immunohistochemical staining to validate RNA findings.
Tumor cells in NE regions are enriched in neural progenitor cell-like cellular states, while CE regions are enriched in mesenchymal-like states. NE glioma cells have similar proportions of proliferative and putative glioma stem cells relative to CE regions, without significant differences in % Ki-67 staining. Tumor cells in NE regions exhibit upregulation of genes previously associated with lower grade gliomas. Our findings in recurrent GBM paralleled some of the findings in a re-analysis of a dataset from primary GBM. Cell-, gene-, and pathway-level analyses of the tumor microenvironment in the NE region reveal relative downregulation of tumor-mediated neovascularization and cell-mediated immune response, but increased glioma-to-nonpathological cell interactions.
This comprehensive analysis illustrates differing tumor and nontumor landscapes of CE and NE regions in high-grade gliomas, highlighting the NE region as an area harboring likely initiators of recurrence in a pro-tumor microenvironment and identifying possible targets for future design of NE-specific adjuvant therapy. These findings also support the aggressive approach to resection of tumor-bearing NE regions.
在高级别胶质瘤全切术后，增强扫描显示的肿瘤主体之外的无强化（NE）浸润性肿瘤细胞是复发的潜在传播者。
我们对15例复发性高级别胶质瘤（n = 5）的标本进行了单核RNA测序，以比较从增强（CE）区域和NE区域前瞻性获取的活检标本。此外，对24份CE活检标本和22份NE活检标本进行了免疫组化染色，以验证RNA结果。
NE区域的肿瘤细胞富含神经祖细胞样细胞状态，而CE区域则富含间充质样状态。与CE区域相比，NE胶质瘤细胞中增殖性和假定的胶质瘤干细胞比例相似，Ki-67染色百分比无显著差异。NE区域的肿瘤细胞表现出先前与低级别胶质瘤相关的基因上调。我们在复发性胶质母细胞瘤中的发现与对原发性胶质母细胞瘤数据集重新分析中的一些发现相似。对NE区域肿瘤微环境的细胞、基因和通路水平分析显示，肿瘤介导的新生血管形成和细胞介导的免疫反应相对下调，但胶质瘤与非病理细胞的相互作用增加。
这项综合分析阐明了高级别胶质瘤中CE和NE区域不同的肿瘤和非肿瘤情况，突出了NE区域是肿瘤微环境中可能隐藏复发起始因素的区域，并确定了未来设计NE特异性辅助治疗的可能靶点。这些发现也支持对包含肿瘤的NE区域采取积极的切除方法。
