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: 10330285
• 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/10330285
• 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; 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; Property; Protein-Serine-Threonine Kinases; RAS Superfamily Proteins; Radio; Recurrence; Regulation; Reporting; Resistance; Role; STAT3 gene; 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.

目前胶质母细胞瘤（GBM）的手术和放化疗护理标准不足， 没有改善预后。越来越多的证据表明，使用当前化疗药物的失败 （替莫唑胺，TMZ）和放射治疗GBM和由此产生的高肿瘤复发归因于 神经胶质瘤干细胞（GSC）的一个小亚群的存在，其特征是它们的干细胞- 比如财产和攻击性行为在缺氧条件下，GSC增加了几个Notch的激活， 这些基因具有预后意义，因为上调的Notch基因与较差的存活率相关。凹口 信号传导在GSC中高度活跃，抑制分化，维持干细胞样特性，因此， 负责GBM肿瘤发生和干性。我们的项目强调瞬时受体电位melastatin- 相关蛋白7（TRPM 7）在Notch信号传导和胶质瘤治疗失败中的作用。TRPM 7编码一个Ca 2+可渗透的 在其羧基末端与丝氨酸/苏氨酸激酶融合的非选择性阳离子通道。我们小组发现， 抑制TRPM 7通道抑制恶性人神经胶质瘤的增殖、迁移和侵袭， 这表明TRPM 7通道可能代表了一种新的和有前途的治疗干预靶点， 恶性神经胶质瘤此外，TRPM 7对人脑胶质瘤细胞增殖和侵袭的影响也是研究的热点之一。 由多种机制介导。TRPM 7调节miR-28- 5 p表达，从而抑制细胞增殖 并通过靶向Ras相关蛋白Rap 1b在胶质瘤细胞中的侵袭。特别是，我们的团队发现TRPM 7 通道通过STAT 3和Notch信号通路调节GSC的生长和增殖。此外该 该提案中的初步数据表明，TRPM 7表达减少与活性降低相关， Notch 1受体的Notch 1胞内结构域（NICD）和GSC标志物CD 133表达的降低， 神经胶质瘤细胞系/xenoline测试。我们的结果表明TRPM 7在大多数胶质瘤中调节Notch通路 细胞系/xenoline，尽管胶质瘤的生物学特性具有高度异质性和变异性。在这 我们假设TRPM 7分子通路在功能上与Notch诱导的干性相关， TRPM 7可能是一个新的GBM药物靶点。在这个项目中，我们将利用患者来源的Xenolines（PDX）， 密切模拟体内真实的细胞和组织的生物学和生理学特征，以检验我们的假设。 目的1：确定TRPM 7在GBM PDX和PDX-1中调节Ca 2+和Mg 2+稳态的作用。 GSC。目的2：研究TRPM 7调控的Notch信号通路在胶质瘤发生发展中的作用 PDX和PDX-GSC可维持GSC的自我更新和致瘤性。目标3：调查 靶向TRPM 7是否减少小鼠PDX神经胶质瘤模型中的肿瘤生长并使肿瘤对TMZ敏感， 介导的凋亡。完成这项研究将描绘TRPM 7在肿瘤中的分子机制。 神经胶质瘤肿瘤发生和干性的发展和进展，以及开发TRPM 7作为一种新的神经胶质瘤抑制剂。 胶质瘤患者的药物靶点。