Understanding methionine metabolism and its therapeutic potential in cancer

了解蛋氨酸代谢及其在癌症中的治疗潜力

• 批准号: 10598595
• 负责人: Xia Gao
• 金额: $ 24.9万
• 依托单位: BAYLOR COLLEGE 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: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598595
• 关键词: ATAC-seq; Adjuvant; Adjuvant Therapy; Affect; Betaine; Biochemical Pathway; Biochemistry; Bioinformatics; CRISPR/Cas technology; Cancer Model; Cancer cell line; Carbon; ChIP-seq; Colorectal Cancer; Complement; Cysteine; Cysteine Metabolism Pathway; DNA; DNA Methylation; Data; Diet; Dietary Intervention; Enzymes; Epigenetic Process; Equilibrium; Essential Amino Acids; Evolution; Exhibits; FRAP1 gene; Fluorouracil; Future; Gene Expression; Generations; Genes; Genetic; Genetic Screening; HCT116 Cells; Health; Human; In Vitro; Insecta; KRASG12D; Laboratories; Learning; Liver; Longevity; Malignant Neoplasms; Mammals; Mediating; Metabolic; Metabolic Pathway; Metabolism; Methionine; Methionine Metabolism Pathway; Methylation; Modeling; Molecular; Mus; Nature; Nutritional; Nutritional Requirements; Obesity; Oncogenes; Outcome; Oxidation-Reduction; PIK3CG gene; Phase; Physiology; Plasma; Property; Protein Biosynthesis; Radiation; Radiation therapy; Reaction; Regulation; Role; S-Adenosylhomocysteine; S-Adenosylmethionine; Soft tissue sarcoma; Sulfur; Supplementation; TP53 gene; Therapeutic; Tissues; Training; Tumor Suppressor Genes; Workload; anti-cancer; auxotrophy; bisulfite sequencing; cancer cell; cancer therapy; career; chemotherapy; clinical application; colon cancer cell line; colon cancer patients; colorectal cancer treatment; cost effective; dietary; dietary restriction; drug development; epigenomics; histone methylation; improved; insulin sensitivity; metabolomics; new therapeutic target; novel therapeutics; patient derived xenograft model; pharmacologic; response; sarcoma; targeted cancer therapy; therapy development; transcriptome sequencing; tumor; tumor growth; tumor metabolism; tumor progression

Cancers have different nutritional requirements from their healthy counterparts. Herein, targeting the enzymes and thus the metabolic networks that constitute these different metabolic requirements is attracting numerous drug development efforts. While targeting enzymes in cancer-specific metabolic pathways has been successful, whether metabolism can be affected to similar extents by nutritional manipulation in specific and controlled manners is largely unknown. Methionine availability affects one-carbon cycle flux, DNA and histone methylation and thus epigenetic programming. Dietary methionine restriction (MR) also promotes metabolic health and extends insect and mammalian lifespan, two anti-cancer features. Thus, we hypothesize that dietary MR could inhibit tumor growth and enhance anti-cancer therapy. Our preliminary data show that dietary MR, a cost-effective approach, alters plasma methionine effectively in both healthy mice and humans. MR mediates promising tumor outcomes: in two RAS-driven colorectal cancer (CRC) patient-derived xenografts (PDX) models, it delays tumor growth and sensitizes tumor to 5-Fluorouracil, a frontline chemotherapy for CRC; and in an autochthonous KRASG12D+/-;TP53-/- soft tissue sarcoma model, it reaches a striking synergistic effect with radiation. In these models, cysteine and methionine metabolism is the most impacted metabolic pathway in the tumor and the plasma. However, the molecular mechanisms by which dietary MR interacts with metabolism and eventually mediates tumor outcome are unknown. To explore the mechanisms, I propose to focus on CRC PDX models through the following two aims. In Aim 1, I will first employ a state of the art metabolomics approach established in our laboratory to evaluate the metabolic alterations in tumor and non- tumor tissues by dietary MR or a combination of MR and 5-FU. Upon consolidation of the findings in vitro, I will conduct dietary interventions by supplementing cysteine or betaine to determine the contribution of methionine as a sulfur donor and a one-carbon donor to tumor growth in CRC PDX models, respectively. In Aim 2, I will first characterize the epigenetic and genetic adaptions to dietary MR in tumor and CRC cell linesusing bisulfite sequencing, ATAC- seq, ChIP-seq, and RNA-seq. With these data, I will construct a metabolic network and perform a functional screen of metabolic pathway genes using CRISPR/Cas9 technology. The outcome will reveal the metabolic, genetic, and epigenetic mechanisms underlying dietary MR-mediated tumor inhibition alone and in adjuvant with 5-FU in CRC. It is also anticipated to provide target metabolite and genes for future hypothesis generation and novel therapy targeting cancer metabolism.

癌症与健康癌症有不同的营养需求。在此处， 靶向酶，从而靶向构成这些不同代谢的代谢网络 的要求正在吸引众多药物开发工作。在靶向酶的同时 癌症特异性代谢途径已成功，代谢是否会受到影响 通过以特定和受控方式进行营养控制来达到类似程度主要是 未知。蛋氨酸可用性影响单碳循环通量、DNA 和组蛋白甲基化 从而进行表观遗传编程。饮食蛋氨酸限制（MR）也促进新陈代谢 保健和延长昆虫和哺乳动物的寿命、抗癌两大功能。因此，我们 假设饮食 MR 可以抑制肿瘤生长并增强抗癌治疗。我们的 初步数据表明，饮食 MR 是一种经济有效的方法，可改变血浆蛋氨酸 对健康小鼠和人类均有效。 MR 介导有希望的肿瘤结果：在两个方面 RAS 驱动的结直肠癌 (CRC) 患者来源的异种移植物 (PDX) 模型，可延缓肿瘤发生 生长并使肿瘤对 5-氟尿嘧啶（CRC 的一线化疗药物）敏感；并在一个 本土KRASG12D+/-;TP53-/-软组织肉瘤模型，它达到了惊人的 与辐射有协同作用。在这些模型中，半胱氨酸和蛋氨酸代谢是 肿瘤和血浆中受影响最大的代谢途径。然而，分子 饮食 MR 与代谢相互作用并最终介导肿瘤的机制 结果未知。为了探索其中的机制，我建议重点关注 CRC PDX 模型 通过以下两个目标。在目标 1 中，我将首先采用最先进的代谢组学 我们实验室建立的方法来评估肿瘤和非肿瘤细胞的代谢变化 通过饮食 MR 或 MR 和 5-FU 组合来观察肿瘤组织。合并后 根据体外研究结果，我将通过补充半胱氨酸或甜菜碱来进行饮食干预 确定蛋氨酸作为硫供体和一碳供体对肿瘤的贡献 CRC PDX 模型的增长。在目标 2 中，我将首先描述表观遗传和 使用亚硫酸氢盐测序、ATAC- 肿瘤和结直肠癌细胞系对饮食 MR 的遗传适应 seq、ChIP-seq 和 RNA-seq。有了这些数据，我将构建一个代谢网络并执行 使用 CRISPR/Cas9 技术对代谢途径基因进行功能筛选。结果 将揭示饮食 MR 介导的代谢、遗传和表观遗传机制 CRC 中单独和与 5-FU 辅助治疗的肿瘤抑制作用。预计还将提供目标 用于未来假设生成和针对癌症的新疗法的代谢物和基因 代谢。