Leveraging Gα12 signaling to treat glioblastoma

利用 Gα12 信号传导治疗胶质母细胞瘤

基本信息

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
项目类别：
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

项目摘要

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.

抽象的胶质母细胞瘤多形是最具侵略性的原发性脑肿瘤之一，患有令人沮丧的预后任务治疗的进步在过去几十年中。患者生存不足是由一段时间后，疾病复发。 GBM是一种高度侵入性的肿瘤，它使得手术衰退困难。 G蛋白偶联受体的能力越来越多地认可调节肿瘤生长。这些受体中的许多通过耦合与α发出信号异三聚体G蛋白GA12的亚基。在癌症中GBM的计算机审问基因组地图集揭示了GNA12的上调，该基因编码G⍺12，伴随的基因通过该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神经胶质瘤干细胞（GSC）中靶向G⍺12会减弱肿瘤细胞自我更新，干细胞基因的表达和侵袭。一致的G⍺12敲除（KD）减少了体内原位植入GSC细胞的肿瘤的侵袭。相互， G⍺12的化学发生激活增加了侵袭。由RNA SEQ评估的G⍺12KD肿瘤显示细胞粘附和迁移基因的表达降低，并增加胸部基因的表达。观察到的迁移行为和基因表达的变化表明G⍺12信号传导促进了隆式至间质转变。证据 G⍺12信令调节转录程序的干性和侵袭GSC的识别这是用于热干预的潜在信号节点。手术然后进行辐射治疗是GBM的护理标准。降低了干和侵入性，相关具有更高的额度状态，可以预测对放射疗法的敏感性，这将反过来可以改善疾病的复发和对健康脑组织的损害。我们的短期目的是提供证据表明缺乏细胞中GSC对辐射治疗的敏感性增强 G⍺12信号传导。我们将在细胞培养和肿瘤轴承中使用GSC的单剂量照射使用图像引导的辐照小鼠。我们的创新方法利用了新发现的 G⍺12对改善GBM治疗的肿瘤生长和侵入性的作用。评估能力在人类患者衍生的神经胶质瘤细胞中，通过G⍺12信号的封锁引起的放射敏化，使用图像引导的辐照与精确药物的方法一致。那，我们的发现可能会影响抗性肿瘤的辐射治疗并改善GBM患者的存活。如果成功，我们的研究将是第一个证明靶向G⍺12信号传导的好处的研究与辐射相关以治疗GBM并将实施G⍺12耦合受体及其转录调节的基因靶标是治疗干预的潜在点。