TRPM7 induces tumorigenesis and stemness through Notch activation in glioma

TRPM7 通过 Notch 激活神经胶质瘤诱导肿瘤发生和干细胞性

• 批准号: 10608118
• 负责人: Mingli Liu
• 金额: $ 35.5万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-11 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608118
• 关键词: Aggressive behavior; Apoptosis; Biologic Characteristic; Biological; Cations; Cell Proliferation; Cells; Central Nervous System Neoplasms; Data; Development; Down-Regulation; Drug Targeting; Failure; Gene Silencing; Genes; Glioblastoma; Glioma; Heterogeneity; Homeostasis; Human; Hypoxia; Infiltration; Invaded; Ligands; MGMT gene; Maintenance; Malignant - descriptor; Malignant Glioma; Malignant neoplasm of central nervous system; Mediating; Modeling; Molecular; Mus; Notch Signaling Pathway; Operative Surgical Procedures; Pathway interactions; Patients; Permeability; Phosphotransferases; Physiological; Prognosis; Proliferating; Property; Protein-Serine-Threonine Kinases; RAS Superfamily Proteins; Radiation therapy; Recurrent tumor; Regulation; Reporting; Resistance; Role; STAT3 gene; Serine; Signal Transduction; Small Interfering RNA; System; Testing; Therapeutic Intervention; Tissues; Trace metal; Treatment Failure; Tumorigenicity; Variant; Vertebrates; Xenograft Model; aldehyde dehydrogenase 1; chemoradiation; glioma cell line; improved; in vivo; migration; molecular subtypes; nanoparticle; new therapeutic target; notch protein; novel; overexpression; prognostic; receptor; response; self-renewal; standard of care; stem; stem cell biomarkers; stem cell growth; stem cells; stem-like cell; stemness; targeted treatment; temozolomide; tumor; tumor growth; tumor xenograft; tumorigenesis

The current standard of care of surgery and radiochemotherapy for glioblastomas (GBM) is inadequate and has not resulted in improved prognosis. Accumulating evidences show that the failure of using current chemo (temozolomide, TMZ)- and radio- therapies to treat GBM and the resultant high tumor recurrence are attributed to the presence of a small subpopulation of glioma stem cells (GSC), which is characterized by their stem cell- like properties and aggressive behavior. Under hypoxic conditions, GSC increase the activation of several Notch genes, which hold a prognostic implication, as upregulated Notch genes are associated with poor survival. Notch signaling is highly active in GSC, inhibits differentiation, maintains stem-like properties, and, therefore, is responsible for GBM tumorigenesis and stemness. Our project highlights transient receptor potential melastatin- related-7 (TRPM7)’s role in Notch signaling and glioma treatment failure. TRPM7 encodes a Ca2+ permeable nonselective cation channel fused with a serine/threonine kinase at its carboxyl terminus. Our group found that the suppression of TRPM7 channels inhibits proliferation, migration, and invasion of malignant human gliomas, indicating that TRPM7 channels may represent a novel and promising target for therapeutic intervention of malignant glioma. Furthermore, the effect of TRPM7 on the proliferation and invasion of human glioma cell is mediated by multiple mechanisms. TRPM7 regulates miR-28-5p expression, which suppresses cell proliferation and invasion in glioma cells by targeting Ras-related protein Rap1b. In particular, our group found that TRPM7 channels regulate GSC growth and proliferation through STAT3 and Notch signaling pathways. In addition, the preliminary data in this proposal show that decreased expression of TRPM7 is correlated with decreased active Notch1 intracellular domain (NICD) from the Notch1 receptor and reduced GSC marker CD133 expression in the glioma cell lines/xenoline tested. Our results indicate that TRPM7 regulates the Notch pathway in most glioma cell lines/xenoline despite the high heterogeneity and variations in glioma’s biological characteristics. In this proposal, we hypothesize that TRPM7 molecular pathway is functionally connected to Notch-induced stemness, and TRPM7 may be a novel GBM drug target. In this project, we will utilize patient-derived xenolines (PDX) that closely mimics the biological and physiological features of in vivo real cells and tissues to test our hypothesis. Aim 1: Determine the role of TRPM7 in the regulation of Ca2+ and Mg2+ homeostasis in GBM PDX and PDX- GSC. Aim 2: Determine the role of the Notch signaling pathway regulated by TRPM7 in the progression of glioma and maintenance of self-renewal and tumorigenicity of GSC using PDX and PDX-GSC. Aim 3: Investigate whether targeting TRPM7 reduces tumor growth in mouse PDX glioma models and sensitizes tumor to TMZ- mediated apoptosis. Accomplishing this study will delineate the molecular mechanisms of TRPM7 in the development and progression of glioma tumorigenesis and stemness, as well as develop TRPM7 as a novel drug target for glioma patients.

目前对胶质母细胞瘤(GBM)的手术和放化疗的护理标准是不够的，而且 不能改善预后。越来越多的证据表明，使用目前化疗的失败 替莫唑胺(替莫唑胺，TMZ)--和放射疗法治疗GBM和由此导致的高肿瘤复发率被归因于 由于存在一小部分胶质瘤干细胞(GSC)，这是其干细胞的特征- 比如属性和攻击性行为。在低氧条件下，GSC可增加几种Notch的活性 具有预后意义的基因，如上调的Notch基因与较差的存活率有关。凹槽 信号在GSC中高度活跃，抑制分化，维持干细胞样特性，因此 负责基底膜肿瘤的发生和茎的形成。我们的项目突出了瞬时受体潜能-- 相关蛋白7(TRPM7)S在Notch信号转导和脑胶质瘤治疗失败中的作用TRPM7编码一种钙离子可渗透的 非选择性阳离子通道在其羧基末端与丝氨酸/苏氨酸激酶融合。我们小组发现 抑制TRPM7通道抑制恶性人脑胶质瘤的增殖、迁移和侵袭， 提示TRPM7通道可能是一种新的、有希望的治疗靶点。 恶性胶质瘤。此外，TRPM7对人脑胶质瘤细胞增殖和侵袭的影响 由多种机制调停。TRPM7调节miR-28-5p表达，抑制细胞增殖 并通过靶向RAS相关蛋白Rap1b侵袭胶质瘤细胞。特别是，我们的团队发现TRPM7 通道通过STAT3和Notch信号通路调节GSC的生长和增殖。此外， 该方案中的初步数据显示，TRPM7表达减少与活性降低相关 Notch1受体的NOTCH1胞内区(NICD)和GSC标志物CD133的表达降低 神经胶质瘤细胞系/杂环磷胆碱检测。我们的结果表明，TRPM7在大多数胶质瘤中调节Notch通路 尽管胶质瘤的生物学特性具有高度的异质性和多样性。在这 建议，我们假设TRPM7分子通路在功能上与Notch诱导的茎有关， TRPM7可能是一种新的GBM药物靶点。在这个项目中，我们将利用患者衍生的异烟肼(PDX)， 通过模拟体内真实细胞和组织的生物和生理特征来验证我们的假说。 目的1：确定TRPM7在调节GBM、PDX和PDX细胞内钙、镁稳态中的作用。 GSC.目的2：确定TRPM7调控的Notch信号通路在脑胶质瘤发生发展中的作用 使用PDX和PDX-GSC维持GSC的自我更新和致瘤性。目标3：调查 靶向TRPM7是否能减少小鼠PDX胶质瘤模型中肿瘤的生长并增强肿瘤对TMZ的敏感性 介导的细胞凋亡。这项研究的完成将勾勒出TRPM7在体内的分子机制。 脑胶质瘤发生发展与干细胞分化及TRPM7作为新基因的研究进展 针对胶质瘤患者的药物靶点。