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: 10554637
• 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/10554637
• 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; Outcome; Oxidation-Reduction; Pharmacology; Phase; Physiology; Plasma; Property; Protein Biosynthesis; Radiation; Radio; Reaction; Regulation; Role; S-Adenosylmethionine; Soft tissue sarcoma; Sulfur; Supplementation; TP53 gene; Therapeutic; 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; cost effective; dietary; dietary restriction; drug development; epigenomics; histone methylation; improved; insulin sensitivity; metabolomics; new therapeutic target; novel therapeutics; patient derived xenograft model; 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.

癌症患者的营养需求与健康患者不同。在此,