Leveraging Gα12 signaling to treat glioblastoma

利用 Gα12 信号传导治疗胶质母细胞瘤

• 批准号: 10649241
• 负责人: Olga Chaim
• 金额: $ 7.9万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2024-03-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10649241
• 关键词: Attenuated; Behavior; Brain; Cell Adhesion; Cell Culture Techniques; Cell Death Induction; Cell Line; Cell Survival; Cells; Coupled; Coupling; Disease remission; Dose; Engraftment; Exposure to; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GNA12 gene; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Transcription; Glioblastoma; Glioma; Goals; Heterotrimeric G Protein Subunit; Human; Implant; In Vitro; Invaded; Label; Luciferases; Malignant neoplasm of brain; Mediating; Mesenchymal; Mus; Neurosphere; Operative Surgical Procedures; Patients; Predisposition; Primary Brain Neoplasms; Prognosis; Radiation; Radiation Tolerance; Radiation therapy; Radiosensitization; Receptor Signaling; Recurrence; Recurrent disease; Reporter; Research; Resistance; Risk; Role; Signal Pathway; Signal Transduction; Testing; The Cancer Genome Atlas; Therapeutic Intervention; Tumor Stem Cells; Up-Regulation; Xenograft procedure; brain tissue; cell growth; cell motility; designer receptors exclusively activated by designer drugs; gain of function; genetic approach; image guided; improved; in silico; in vivo; innovation; irradiation; knock-down; neoplastic cell; overexpression; precision medicine; programs; radiation response; receptor; response; self-renewal; small hairpin RNA; standard of care; stem cell genes; stem cells; stemness; transcriptome sequencing; tumor; tumor growth

Abstract Glioblastoma multiforme, one of the most aggressive primary brain tumors, has a dismal prognosis despite treatment advancements in the past decades. Low patient survival is driven by disease recurrency after a period of remission. GBM is a highly invasive tumor, which makes surgical recession difficult. G-protein coupled receptors are increasingly recognized for their ability to regulate tumor growth. Many of these receptors signal through their coupling to the alpha subunit of the heterotrimeric G-protein Ga12. In silico interrogation of GBM in The Cancer Genome Atlas reveals marked upregulation of GNA12, the gene encoding G⍺12, concomitant with overexpression of G-protein coupled receptors (GPCRs) that signal through this G-protein. We recently determined that targeting G⍺12 in human glioma stem cells (GSCs) attenuates tumor cell self-renewal, expression of stem cell genes, and invasion. Concordantly G⍺12 knockdown (KD) reduced invasion of tumors from orthotopically engrafted GSC cells in vivo. Reciprocally, chemogenetic activation of G⍺12 increased invasion. G⍺12 KD tumors assessed by RNA seq showed reduced expression of cell adhesion and migration genes, as well as increased expression of proneural genes. The observed changes in migratory behavior and gene expression suggest that G⍺12 signaling promotes a proneural-to-mesenchymal transition. The evidence that G⍺12 signaling regulates transcriptional programs for stemness and invasion of GSCs identifies this as a potential signaling node for therapeutic intervention. Surgery followed by radiation therapy is the standard of care for GBM. Decreases in stemness and invasiveness, associated with a more proneural state, would be predictive of improved sensitivity to radiation therapy which could in turn ameliorate disease recurrence and damage to healthy brain tissue. Our short-term goal is to provide evidence for enhanced GSC susceptibility to radiation treatment in cells lacking G⍺12 signaling. We will use single dose irradiation of GSCs in cell culture and in tumor bearing mice using image-guided irradiation. Our innovative approach leverages the newly discovered role of G⍺12 on tumor growth and invasiveness to improve GBM treatment. The ability to evaluate radiosensitization, elicited by blockade of G⍺12 signals, in human patient derived glioma cells, using image-guided irradiation is consistent with precision medicine approaches. Thus, our findings could impact radiation treatment of resistant tumors and improve GBM patient survival. If successful, our studies will be the first to demonstrate the benefit of targeting G⍺12 signaling in association with radiation to treat GBM and will implicate G⍺12-coupled receptors and their transcriptionally regulated gene targets as potential points of therapeutic intervention.

抽象的 多形性胶质母细胞瘤是最具侵袭性的原发性脑肿瘤之一，其发病率令人沮丧 尽管过去几十年来治疗取得了进步，但预后仍然不佳。患者生存率低的原因是 缓解一段时间后疾病复发。 GBM 是一种高度侵袭性的肿瘤，这使得 手术衰退困难。 G 蛋白偶联受体的能力越来越受到认可 来调节肿瘤生长。许多这些受体通过与 α 的偶联来发出信号 异源三聚体 G 蛋白 Ga12 的亚基。癌症中 GBM 的计算机模拟研究 基因组图谱显示 GNA12（编码 G⍺12 的基因）显着上调，同时 G 蛋白偶联受体 (GPCR) 过度表达，通过该 G 蛋白发出信号。 我们最近确定，靶向人类神经胶质瘤干细胞 (GSC) 中的 G⍺12 可减弱肿瘤 细胞自我更新、干细胞基因表达和侵袭。一致地 G⍺12 击倒 (KD)减少体内原位移植的GSC细胞对肿瘤的侵袭。反过来， G⍺12 的化学遗传学激活增加了侵袭。通过 RNA seq 评估 G⍺12 KD 肿瘤 显示细胞粘附和迁移基因的表达减少，以及细胞粘附和迁移基因的表达增加 原神经基因的表达。观察到的迁移行为和基因表达的变化 表明 G⍺12 信号传导促进原神经向间质的转变。证据表明 G⍺12 信号传导调节 GSC 干性和侵袭的转录程序 这是治疗干预的潜在信号节点。手术后进行放射治疗 治疗是 GBM 的标准治疗。干性和侵袭性的减少，相关 具有更原神经状态，将预示着对放射治疗的敏感性提高 反过来可以改善疾病复发和对健康脑组织的损害。我们的短期 目标是为缺乏放射治疗的细胞中的 GSC 敏感性增强提供证据。 G⍺12 信号。我们将在细胞培养和荷瘤中使用 GSC 的单剂量照射 使用图像引导照射的小鼠。我们的创新方法利用了新发现的 G⍺12 对肿瘤生长和侵袭的作用，以改善 GBM 治疗。评估能力 在人类患者来源的神经胶质瘤细胞中，通过阻断 G⍺12 信号而引起放射增敏， 使用图像引导照射与精准医学方法一致。因此，我们的 研究结果可能会影响耐药肿瘤的放射治疗并提高 GBM 患者的生存率。 如果成功，我们的研究将首次证明靶向 G⍺12 信号传导的益处 与放射治疗 GBM 相关，并涉及 G⍺12 偶联受体及其 转录调控的基因靶标作为治疗干预的潜在点。