Department of Neurosurgery, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Gyeonggi-do, Republic of Korea.
Department of Pathology, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Gyeonggi-do, Republic of Korea.
Cancer Immunol Immunother. 2022 Dec;71(12):3013-3027. doi: 10.1007/s00262-022-03222-4. Epub 2022 May 23.
Glioblastoma multiforme (GBM) is an aggressive malignant primary brain tumor. Wnt/β-catenin is known to be related to GBM stemness. Cancer stem cells induce immunosuppressive and treatment resistance in GBM. We hypothesized that Wnt/β-catenin-related genes with immunosuppression could be related to the prognosis in patients with GBM.
We obtained the clinicopathological data of 525 patients with GBM from the brain cancer gene database. The fraction of tumor-infiltrating immune cells was evaluated using in silico flow cytometry. Among gene sets of Wnt/β-catenin pathway, Dickkopf-3 (DKK3) gene related to the immunosuppressive response was found using machine learning. We performed gene set enrichment analysis (GSEA), network-based analysis, survival analysis and in vitro drug screening assays based on Dickkopf-3 (DKK3) expression.
In analyses of 31 genes related to Wnt/β-catenin signaling, high DKK3 expression was negatively correlated with increased antitumoral immunity, especially CD8 + and CD4 + T cells, in patients with GBM. High DKK3 expression was correlated with poor survival and disease progression in patients with GBM. In pathway-based network analysis, DKK3 was directly linked to the THY1 gene, a tumor suppressor gene. Through in vitro drug screening, we identified navitoclax as an agent with potent activity against GBM cell lines with high DKK3 expression.
These results suggest that high DKK3 expression could be a therapeutic target in GBM. The results of the present study could contribute to the design of future experimental research and drug development programs for GBM.
多形性胶质母细胞瘤（GBM）是一种侵袭性的恶性原发性脑肿瘤。Wnt/β-catenin 信号通路已知与 GBM 干性相关。癌症干细胞在 GBM 中诱导免疫抑制和治疗耐药性。我们假设与免疫抑制相关的 Wnt/β-catenin 相关基因可能与 GBM 患者的预后相关。
我们从脑肿瘤基因数据库中获得了 525 名 GBM 患者的临床病理数据。使用计算机模拟流式细胞术评估肿瘤浸润免疫细胞的分数。在 Wnt/β-catenin 通路的基因集中，使用机器学习找到了与免疫抑制反应相关的 Dickkopf-3（DKK3）基因。我们基于 Dickkopf-3（DKK3）表达进行了基因集富集分析（GSEA）、网络分析、生存分析和体外药物筛选实验。
在对 31 个与 Wnt/β-catenin 信号相关的基因的分析中，GBM 患者中高 DKK3 表达与抗肿瘤免疫的增加呈负相关，特别是 CD8+和 CD4+T 细胞。高 DKK3 表达与 GBM 患者的不良生存和疾病进展相关。在基于通路的网络分析中，DKK3 与肿瘤抑制基因 THY1 基因直接相关。通过体外药物筛选，我们发现 navitoclax 是一种对高 DKK3 表达的 GBM 细胞系具有强大活性的药物。
这些结果表明，高 DKK3 表达可能是 GBM 的治疗靶点。本研究的结果可能有助于设计未来针对 GBM 的实验研究和药物开发计划。
