Hydrogen sulfide functions as a tumor suppressor in glioblastoma

硫化氢在胶质母细胞瘤中充当肿瘤抑制剂

基本信息

批准号：
10656703
负责人：
CHRISTOPHER Michael HINE
金额：
$ 51.51万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
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 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10656703
关键词：
Acceleration Adult Affect Age Aging Attenuated Biological Availability Brain Cell Maintenance Cell Proliferation Cells Chemicals Clinical Clinical Trials Cues Cysteine Desulfhydrase Data Diagnosis Elderly Enzymes Epigenetic Process FDA approved Generations Genetic Genetically Engineered Mouse Glioblastoma Goals Growth Human Hydrogen Sulfide Hypothyroidism Immunologic Surveillance Immunosuppression Immunotherapy In Vitro Intervention Knock-out Knockout Mice Life Longevity Maintenance Malignant - descriptor Malignant neoplasm of brain Mediating Metabolic Metabolism Methimazole Mitochondria Modeling Molecular Nerve Degeneration Outcome Oxidation-Reduction Patients Pharmaceutical Preparations Pre-Clinical Model Primary Brain Neoplasms Production Progression-Free Survivals Proliferating Propylthiouracil Protein S Proteins Publishing Radio Recurrence Regulation Repression Resistance Role Sampling Signal Transduction Site Specimen Sulfur Amino Acids Tamoxifen Testing Therapeutic Therapeutic Effect Therapeutic Studies Thyroid Gland Thyroid Hormones Time Tissues Tumor Burden Tumor Suppression Tumor Suppressor Proteins Visit age effect aged amino acid metabolism cancer stem cell clinically relevant detection assay dietary experimental study hormonal signals human old age (65+)immune activation immune function improved in vivo juvenile animal metabolic fitness mouse model multimodality neoplastic cell neural novel overexpression patient derived xenograft model pharmacologic pre-clinical prevent programs response self-renewal standard of care stem cell population stem cell self renewal stem cell survival sulfhydration synergism temozolomide therapy resistant treatment strategy tumor tumor growth tumor initiation tumor microenvironment tumorigenic

项目摘要

ABSTRACT: Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. GBM growth and therapeutic resistance are driven by a combination of self-renewing cancer stem cells (CSCs) and an aging- induced tumor-supportive microenvironment. CSCs are regulated by cell intrinsic genetic and epigenetic networks, extrinsic cellular interactions with the surrounding microenvironment, and the interaction between those intrinsic and extrinsic regulatory programs. While multiple molecular mechanisms that drive self-renewal have been identified, the effects of advanced age on CSC maintenance has yet to be explored. Specifically, it is unclear how advanced age alters CSC maintenance and GBM growth. A recently recognized hallmark of advanced age is the shift in sulfur amino acid metabolism that suppresses enzyme-dependent hydrogen sulfide (H2S) generation, signaling, and bioavailability. H2S is a redox-active metabolite that signals through protein S- sulfhydration (R-SSnH) and impacts metabolism, immune activation, and longevity. Its enzymatic production by cystathionine γ-lyase (CGL) is repressed by thyroid hormone (TH). H2S has both pro- and anti-tumorigenic functions that are tumor-type dependent. However, there is limited information on cell intrinsic and tumor microenvironment functions of H2S in GBM. Recently, we modulated H2S levels through dietary and pharmacological interventions and found that H2S functions as a tumor suppressor in GBM and attenuates CSC self-renewal and tumor growth in pre-clinical models. H2S generation and sulfhydration were decreased in human GBM specimens as compared to non-tumor controls. While the data support the hypothesis that H2S functions as a tumor suppressor in GBM, the effects of aging-induced H2S declines on GBM progression and CSCs, and how to reverse this for clinical use, are unexplored. Based on our published findings and new preliminary data, we hypothesize that decreased H2S production during aging promotes CSC initiation, immune suppression, and drives GBM growth but can ultimately be reversed by anti-TH based H2S boosting approaches. We will test this hypothesis through the following aims by integrating our newly developed H2S and sulfhydration detection assays in combination with in vitro and in vivo GBM models that manipulate H2S production via genetic and pharmacological interventions with human samples to provide clinical relevance. Aim 1 tests the hypothesis that aging-induced suppression of CGL-derived H2S accelerates GBM progression. Aim 2 tests the hypothesis that chemically-induced hypothyroidism stimulates CGL to increase systemic and neural H2S production resulting in reduced GBM progression, CSC enrichment, and improved survival in preclinical GBM models. The long-term goal of this project is to interrogate the function of H2S as a GBM tumor suppressor that is lost during aging, while also studying the therapeutic effects of hypothyroid-induced H2S production and signaling to reduce CSC maintenance and immune suppression. Leveraging this axis represents a new strategy for the management of GBM that may synergize with standard of care chemo-, radio-, and immunotherapies.

摘要：胶质母细胞瘤（GBM）是成年人中最常见的恶性原发性脑肿瘤。 GBM增长和热电阻是由自我更新的癌症干细胞（CSC）和衰老的组合驱动的诱导肿瘤支持的微环境。 CSC受细胞固有遗传和表观遗传学调节网络，外在细胞与周围微环境的相互作用以及之间的相互作用那些内在和外在的监管计划。而多种分子机制可以自我更新已经确定了高级年龄对CSC维护的影响尚未探索。具体来说，是尚不清楚高级年龄如何改变CSC的维护和GBM的增长。最近公认的标志高龄是硫氨基酸代谢的转移，可抑制依赖酶的硫化氢（H2S）生成，信号和生物利用度。 H2S是一种氧化还原活性代谢产物，通过蛋白质S-信号硫水（R-SSNH）并影响代谢，免疫激活和寿命。它的酶促生产甲状腺激素（Th）再现。 H2S具有促肿瘤和抗肿瘤肿瘤型的功能依赖。但是，关于细胞固有和肿瘤的信息有限 H2S在GBM中的微环境功能。最近，我们通过饮食和药理干预措施，发现H2S在GBM中充当肿瘤抑制剂，并减弱CSC 临床前模型中的自我更新和肿瘤生长。人类的H2S产生和硫化降低与非肿瘤对照相比，GBM标本。数据支持H2S功能的假设作为GBM中的肿瘤抑制剂，衰老诱导的H2S的影响对GBM进展和CSC的影响下降，以及如何扭转这一点供临床使用，这是出乎意料的。根据我们已发表的发现和新的初步数据我们假设衰老期间H2S的产生降低会促进CSC启动，免疫抑制作用，并驱动GBM增长，但最终可以通过基于反预测的H2S逆转方法。我们将通过以下目标来检验这一假设，通过整合我们新开发的H2S和与操纵H2S的体外和体内GBM模型结合使用硫化检测测定法通过人类样品进行遗传和药物干预措施的生产，以提供临床相关性。目的 1检验以下假设：衰老诱导的CGL衍生的H2S的抑制会加速GBM的进展。目的 2检验了化学诱导的甲状腺功能减退症的假设可刺激CGL增加全身和中性 H2S的产生导致GBM进展，CSC富集和临床前的生存率提高 GBM型号。该项目的长期目标是审问H2S作为GBM肿瘤抑制剂的功能在衰老过程中丢失了，同时还研究了甲状腺功能下诱导的H2S产生的治疗作用和信号传导以减少CSC维护和免疫抑制。利用此轴代表了一种新策略为了管理GBM，可能与标准的护理化学，无线电和免疫疗法协同作用。