The role of serine metabolism on the evolution of oral squamous cell carcinoma

丝氨酸代谢在口腔鳞状细胞癌演变中的作用

• 批准号: 10825875
• 负责人: Stacy Jankowski
• 金额: $ 4.85万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-12 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10825875
• 关键词: Alcohol consumption; Algorithms; Anabolism; Anatomy; Biochemical; Biological; Biological Assay; Carcinoma; Cell Communication; Cell Differentiation process; Cell Line; Cell Lineage; Cells; Chromatin; Chromatin Structure; Clinical; Cluster Analysis; Complex; Coupled; Development; Dietary Intervention; Differentiated Gene; Differentiation Antigens; Dioxygenases; Environment; Enzymes; Epigenetic Process; Epithelium; Evolution; Genes; Genomics; Global Change; Growth; Head and Neck Cancer; Heterogeneity; Histones; Human; Human Papillomavirus; Immunofluorescence Immunologic; Immunohistochemistry; In Vitro; Invaded; Isogenic transplantation; Knowledge; Lead; Lysine; Malignant Epithelial Cell; Malignant Neoplasms; Mesenchymal; Messenger RNA; Metabolism; Modeling; Modification; Morbidity - disease rate; Morphology; Neoplasm Metastasis; Nuclear; Nutrient; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Play; Population; Proliferating; Proliferation Marker; Proteins; Radiation therapy; Repression; Research; Resistance; Role; Science; Serine; Signal Pathway; Starvation; Therapeutic; Tobacco use; Transcription Initiation Site; Validation; Western Blotting; Withdrawal; advanced disease; alpha ketoglutarate; cancer stem cell; cancer therapy; cell motility; chemotherapy; cost effective; demethylation; deprivation; derepression; dietary; dietary restriction; enzyme pathway; epigenomic profiling; epigenomics; histone modification; in vivo; insight; malignant mouth neoplasm; migration; mortality; mouse model; mouth squamous cell carcinoma; neoplastic cell; novel; novel therapeutic intervention; novel therapeutics; precision nutrition; programs; response; side effect; stem; stem cell genes; stem cell population; stemness; success; targeted treatment; therapeutically effective; trait; treatment response; tumor; tumor growth; tumor heterogeneity; tumor progression; tumorigenic; uptake

ABSTRACT Oral squamous cell carcinoma (OSCC) is a devastating malignancy associated with high morbidity, poor survival, and few therapeutic options. OSCC is characterized by heterogeneous cell states, including cancer stem cells (CSCs), which drive metastasis and therapy resistance. Although there has been some modest success with targeted therapies, there remains a need for more effective therapeutic options for OSCC. Increasing evidence has shown that changes in serine metabolism can direct cell fate via epigenomic changes. Endogenous serine synthesis generates a by-product, alpha-ketoglutarate (αKG), which is a co-substrate for nuclear αKG- dependent dioxygenases to demethylate histone marker H3K27me3 and de-repress differentiation genes. We have shown that under serine starvation conditions, metastatic OSCC HSC3 cells slowed proliferation concomitant with a change in morphology from mesenchymal to epithelial, compared to cells grown in complete medium. This was associated with a statistically significant increase in the steady-state mRNA and enzyme levels in the serine synthesis pathway under serine starvation conditions, indicating that HSC3 cells rely on exogenous serine for growth. The observed switch from exogenous serine uptake to endogenous serine synthesis in HSC3 cells was accompanied by an increase in αKG concentration. Furthermore, serine starvation and increased αKG were associated with decrease of repressive histone marker H3K27me3, thus de-repressing terminal epithelial differentiation genes. Simultaneously, there is a decrease in H3K4me3, a marker of open chromatin structure, associated with the promotion of stemness genes and aggressive cancer traits in OSCC. Initial studies into the plasticity of the stem-like identity using the tumorsphere formation assay shows that serine starvation leads to a lack of tumorspheres stability. Our findings suggest that a switch from exogenous serine uptake to the endogenous serine biosynthesis promotes OSCC cell differentiation concomitant with the loss of CSC identity. Given my preliminary studies, I hypothesize that serine deprivation promotes epigenetic changes that inhibit CSCs and OSCC progression to advanced disease. I will investigate our hypotheses through two aims. My first aim will be to determine mechanisms underlying epigenetic modifications in a panel of OSCC cell lines in response to serine deprivation in vitro. This will be investigated through use of migration and invasion assays, in depth tumorsphere analysis, and epigenomic profiling. My second aim will be to define changes in tumor size and tumor cell populations in response to dietary serine restriction in vivo, utilizing a syngeneic 4MOSC1 isograft mouse model of OSCC to interrogate the heterogeneity of tumor cell populations through scRNAseq with biochemical validation. These studies will fill the gap in knowledge how changes in serine metabolism impact the epigenomic environment and provide insight into novel therapeutic options for OSCC.

抽象的 口服鳞状细胞癌（OSCC）是一种毁灭性的恶性肿瘤，与高发病率相关，生存率差， 几乎没有治疗选择。 OSCC的特征是异质细胞态，包括癌干细胞 （CSC），驱动转移和耐药性。尽管在 有针对性的疗法，仍然需要对OSCC进行更有效的治疗选择。越来越多的证据 已经表明，丝氨酸代谢的变化可以通过表观基因组变化引导细胞命运。内源性系列 合成产生副产品，α-酮戊二酸（αkg），这是核αkg-的共基质 脱甲基化组蛋白标志物H3K27ME3和去抑制分化基因的依赖性双氧酶。我们 已经表明，在丝氨酸饥饿条件下，转移性OSCC HSC3细胞减慢了增殖 与完整生长的细胞相比 中等的。这与稳态mRNA和酶的统计学显着增加有关 丝氨酸饥饿条件下的丝氨酸合成途径的水平，表明HSC3细胞依靠 外源性丝氨酸的生长。观察到的从外源丝氨酸摄取到内源丝氨酸的转换 HSC3细胞中的合成是通过αkg浓度升高来完成的。此外，连续饥饿 αkg增加与反射性组蛋白标记物H3K27me3的降低有关，从而取消了抑制 末端上皮分化基因。同时，H3K4Me3有所下降，一个开放的标记 编年素结构，与OSCC中的干性基因促进和侵袭性癌症性状有关。 最初使用肿瘤形成测定法对茎状同一性的可塑性的最初研究表明串行 饥饿导致缺乏肿瘤球稳定性。我们的发现表明从外源连续的转换 对内源性丝氨酸生物合成的摄取可促进OSCC细胞分化与丧失 CSC身份。鉴于我的初步研究，我假设丝氨酸剥夺会促进表观遗传变化 这抑制了CSC和OSCC发展为晚期疾病。我将通过两个调查我们的假设 目标。我的第一个目的是确定OSCC单元组中表观遗传修饰的机制 在体外响应丝氨酸剥夺的线条。这将通过使用迁移和入侵来调查 测定，深度肿瘤分析和表观基因组分析。我的第二个目标是定义更改 肿瘤的大小和肿瘤细胞种群响应饮食中的饮食序列限制，并使用同步性 4MOSC1 OSCC的同类小鼠模型，以通过 具有生化验证的scrnaseq。这些研究将填补知识如何变化的差距 代谢影响表观基因组环境，并为OSCC的新型治疗选择提供了见解。