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.

摘要 多形性胶质母细胞瘤是最具侵袭性的原发性脑肿瘤之一， 尽管在过去的几十年里治疗取得了进展。患者生存率低的原因是 疾病缓解一段时间后又复发。GBM是一种高度侵袭性的肿瘤， 手术后退困难。G蛋白偶联受体越来越多地被认为具有 来调节肿瘤的生长这些受体中的许多通过它们与α受体的偶联来传递信号。 异源三聚体G蛋白Ga 12的亚基。癌症中GBM的计算机审讯 基因组图谱显示GNA12（编码GNA12的基因）的显著上调， 通过该G蛋白发出信号的G蛋白偶联受体（GPCR）的过表达。 我们最近确定，靶向人脑胶质瘤干细胞（GSC）中的G12可以减少肿瘤细胞的增殖， 细胞自我更新、干细胞基因表达和侵袭。和谐的G 12击倒 (KD)减少原位移植的GSC细胞在体内的肿瘤侵袭。反过来说， G β 12的化学发生激活增加了侵袭。通过RNA测序评估的G β 12 KD肿瘤 显示细胞粘附和迁移基因的表达减少， 前神经基因的表达。观察到的迁移行为和基因表达的变化 提示GST12信号传导促进原神经向间充质的转化。的证据 GST12信号转导调节GSC的干细胞性和侵袭的转录程序 这作为治疗干预的潜在信号节点。手术后进行放射治疗 治疗是治疗GBM的标准。干性和侵袭性降低，相关 前神经状态更强的患者，将预示着对放射治疗的敏感性提高， 可以反过来改善疾病复发和对健康脑组织的损害。我们的短期 目的是提供证据，增强GSC对缺乏放射治疗的细胞的敏感性。 G 12信令。我们将在细胞培养和荷瘤中使用单剂量照射GSC 小鼠使用图像引导照射。我们的创新方法利用了新发现的 GBM 12对肿瘤生长和侵袭性的作用，以改善GBM治疗。评估能力 放射增敏，通过阻断G112信号引起，在人患者来源的神经胶质瘤细胞中， 使用图像引导照射与精确医学方法一致。所以我们 这些发现可能会影响耐药肿瘤的放射治疗，并提高GBM患者的生存率。 如果成功的话，我们的研究将是第一个证明靶向G β 12信号转导在治疗糖尿病中的益处的研究。 与放射治疗GBM相关，并将涉及GBM 12偶联受体及其受体。 转录调节基因靶点作为治疗干预的潜在点。