Filippova Natalia, Grimes Jeffrey M, Leavenworth Jianmei W, Namkoong David, Yang Xiuhua, King Peter H, Crowley Michael, Crossman David K, Nabors L Burt
Department of Neurology, Division of Neuro-oncology, UAB, Birmingham, Alabama, USA.
Department of Neurosurgery, Program of Immunology, UAB, Birmingham, Alabama, USA.
Neurooncol Adv. 2022 Sep 15;4(1):vdac149. doi: 10.1093/noajnl/vdac149. eCollection 2022 Jan-Dec.
Tumor cellular and molecular heterogeneity is a hallmark of glioblastoma and underlies treatment resistance and recurrence. This manuscript investigated the myeloid-derived microenvironment as a driver of glioblastoma heterogeneity and provided a pharmacological pathway for its suppression.
Transcriptomic signatures of glioblastoma infiltrated myeloid-derived cells were assessed using R2: genomic platform, Ivy Glioblastoma Spatial Atlas, and single-cell RNA-seq data of primary and recurrent glioblastomas. Myeloid-derived cell prints were evaluated in five PDX cell lines using RNA-seq data. Two immunocompetent mouse glioblastoma models were utilized to isolate and characterize tumor-infiltrated myeloid-derived cells and glioblastoma/host cell hybrids. The ability of an inhibitor of HuR dimerization SRI42127 to suppress TREM1-microenvironment and glioblastoma/myeloid-derived cell interaction was assessed in vivo and in vitro.
TREM1-microenvironment is enriched in glioblastoma peri-necrotic zones. TREM1 appearance is enhanced with tumor grade and associated with poor patient outcomes. We confirmed an expression of a variety of myeloid-derived cell markers, including TREM1, in PDX cell lines. In mouse glioblastoma models, we demonstrated a reduction in the TREM1-microenvironment and glioblastoma/host cell fusion after treatment with SRI42127. In vitro assays confirmed inhibition of cell fusion events and reduction of myeloid-derived cell migration towards glioblastoma cells by SRI42127 and TREM1 decoy peptide (LP17) versus control treatments.
TREM1-myeloid-derived microenvironment promulgates glioblastoma heterogeneity and is a therapeutic target. Pharmacological inhibition of HuR dimerization leads to suppression of the TREM1-myeloid-derived microenvironment and the neoplastic/non-neoplastic fusogenic cell network.
肿瘤细胞和分子异质性是胶质母细胞瘤的一个标志，也是治疗耐药性和复发的基础。本论文研究了髓系来源的微环境作为胶质母细胞瘤异质性的驱动因素，并提供了一种抑制它的药理学途径。
使用R2：基因组平台、Ivy胶质母细胞瘤空间图谱以及原发性和复发性胶质母细胞瘤的单细胞RNA测序数据，评估胶质母细胞瘤浸润的髓系来源细胞的转录组特征。使用RNA测序数据在五种PDX细胞系中评估髓系来源细胞印记。利用两种具有免疫活性的小鼠胶质母细胞瘤模型来分离和表征肿瘤浸润的髓系来源细胞以及胶质母细胞瘤/宿主细胞杂种。在体内和体外评估HuR二聚化抑制剂SRI42127抑制TREM1微环境和胶质母细胞瘤/髓系来源细胞相互作用的能力。
TREM1微环境在胶质母细胞瘤坏死周围区域富集。TREM1的出现随着肿瘤分级而增强，并与患者的不良预后相关。我们在PDX细胞系中证实了包括TREM1在内的多种髓系来源细胞标志物的表达。在小鼠胶质母细胞瘤模型中，我们证明用SRI42127治疗后TREM1微环境以及胶质母细胞瘤/宿主细胞融合减少。体外试验证实，与对照处理相比，SRI42127和TREM1诱饵肽（LP17）可抑制细胞融合事件，并减少髓系来源细胞向胶质母细胞瘤细胞的迁移。
TREM1髓系来源微环境促进了胶质母细胞瘤的异质性，是一个治疗靶点。HuR二聚化的药理学抑制导致TREM1髓系来源微环境以及肿瘤性/非肿瘤性融合细胞网络的抑制。
