Vishnoi Monika, Dereli Zeynep, Yin Zheng, Kong Elisabeth K, Kinali Meric, Thapa Kisan, Babur Ozgun, Yun Kyuson, Abdelfattah Nourhan, Li Xubin, Bozorgui Behnaz, Rostomily Robert C, Korkut Anil
Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX, 77030 USA.
Department of Neurosurgery, University of Washington School of Medicine, Seattle WA, 98195.
bioRxiv. 2023 Jun 8:2023.06.06.543903. doi: 10.1101/2023.06.06.543903.
Interactions among tumor, immune and vascular niches play major roles in driving glioblastoma (GBM) malignancy and treatment responses. The composition, heterogeneity, and localization of extracellular core matrix proteins (CMPs) that mediate such interactions, however, are not well understood. Here, we characterize functional and clinical relevance of genes encoding CMPs in GBM at bulk, single cell, and spatial anatomical resolution. We identify a "matrix code" for genes encoding CMPs whose expression levels categorize GBM tumors into matrisome-high and matrisome-low groups that correlate with worse and better survival, respectively, of patients. The matrisome enrichment is associated with specific driver oncogenic alterations, mesenchymal state, infiltration of pro-tumor immune cells and immune checkpoint gene expression. Anatomical and single cell transcriptome analyses indicate that matrisome gene expression is enriched in vascular and leading edge/infiltrative anatomic structures that are known to harbor glioma stem cells driving GBM progression. Finally, we identified a 17-gene matrisome signature that retains and further refines the prognostic value of genes encoding CMPs and, importantly, potentially predicts responses to PD1 blockade in clinical trials for GBM. The matrisome gene expression profiles may provide biomarkers of functionally relevant GBM niches that contribute to mesenchymal-immune cross talk and patient stratification to optimize treatment responses.
肿瘤、免疫和血管微环境之间的相互作用在驱动胶质母细胞瘤（GBM）的恶性进展和治疗反应中起着主要作用。然而，介导这种相互作用的细胞外核心基质蛋白（CMPs）的组成、异质性和定位尚不清楚。在这里，我们在整体、单细胞和空间解剖分辨率水平上，对GBM中编码CMPs的基因的功能和临床相关性进行了表征。我们确定了编码CMPs的基因的“基质编码”，其表达水平将GBM肿瘤分为基质体高和基质体低两组，分别与患者较差和较好的生存率相关。基质体富集与特定的驱动致癌改变、间充质状态、促肿瘤免疫细胞浸润和免疫检查点基因表达有关。解剖学和单细胞转录组分析表明，基质体基因表达在血管以及已知含有驱动GBM进展的胶质瘤干细胞的前沿/浸润性解剖结构中富集。最后，我们确定了一个17基因的基质体特征，该特征保留并进一步细化了编码CMPs的基因的预后价值，重要的是，在GBM的临床试验中可能预测对PD1阻断的反应。基质体基因表达谱可能提供功能相关的GBM微环境的生物标志物，有助于间充质-免疫相互作用和患者分层，以优化治疗反应。
