Decoding tumor metabolic and immunologic interactions driving racial disparity in African American patients with bladder cancer.

解码肿瘤代谢和免疫相互作用导致非裔美国膀胱癌患者的种族差异。

• 批准号: 10718787
• 负责人: Jianjun Gao
• 金额: $ 64.54万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10718787
• 关键词: Address; Affect; African American; American; Automobile Driving; Basic Science; Bioinformatics; Biological; Biology; Biometry; Cancer Biology; Cancer Patient; Cell Communication; Cell Line; Citric Acid Cycle; Clinical; Clinical Management; Complex; Coupled; Cytometry; Data; Dependence; Disparity; Electron Transport; Energy Metabolism; European; Fatty Acids; Foundations; Gene Expression Profiling; Genes; Genetic; Glutaminase; Glutamine; Goals; Growth; Histocytochemistry; Human; Image; Immune signaling; Immunologics; Immunotherapeutic agent; Immunotherapy; In Vitro; Inferior; Institution; Interferon Type II; Interferon alpha; Interferons; Intervention; Investigation; Knock-out; Link; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mass Spectrum Analysis; Measures; Mediating; Mediator; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Modeling; Molecular; NADH dehydrogenase (ubiquinone); Neoplasm Metastasis; Outcome; Pathway interactions; Patients; Pattern; Pre-Clinical Model; Production; Recurrent disease; Research; Respiration; Role; Signal Pathway; Signal Transduction; Socioeconomic Status; Testing; The Cancer Genome Atlas; Therapeutic; Tissues; Tumor Promotion; Tumor-infiltrating immune cells; Work; Xenograft procedure; cancer gene expression; cancer health disparity; cancer type; carboxylate; carboxylation; checkpoint therapy; clinically relevant; cohort; combinatorial; experimental study; field study; follow-up; genome-wide; health care availability; humanized mouse; immune activation; immunoregulation; improved; in vivo; inhibitor; inhibitor therapy; insight; knock-down; loss of function; mass spectrometric imaging; metabolomics; mitochondrial metabolism; mortality; mouse model; overexpression; preclinical study; protein expression; racial disparity; response; single-cell RNA sequencing; therapeutic evaluation; transcriptomics; treatment response; tumor; tumor growth; tumor immunology; tumor progression; tumor-immune system interactions; tumorigenesis

Project Summary African American (AA) bladder cancer (BLCA) patients have worse survival and oncologic outcomes compared to their European American (EA) counterparts. We contend that the lower survival of AA patients is driven in part by altered tumor-specific biological activities. We have identified through mass spectrometry, genome-wide transcriptomics, and functional biology in ancestry-verified cell lines and tumors from AA and EA BLCA patients a pattern of mitochondrial dysregulation and immune activation disproportionately present in AA BLCA patients. Based on this insight, we first characterized downstream metabolic changes and discovered that mitochondrial complex I dysregulation was observed more frequently in AA BLCA patients and correlated with more aggressive BLCA. In addition, targeted inhibition of complex I resulted in improved cancer outcomes in a preclinical model. Moreover, we found that AA tumors containing increased complex I activity demonstrated a higher glutamine flux into the TCA cycle by activation of GLS1, leading to accumulation of fatty acids via reductive carboxylation. Furthermore, AA tumors with increased mitochondrial complex 1 activity showed enhanced expression of the key complex I gene NDUFB8. Knockdown (KD) of NDUFB8 resulted in reduced mitochondrial complex 1 activity, glutamine metabolism, ATP production, and regression of BLCA growth. Lastly, we found that AA tumors with increased mitochondrial complex 1 activity also demonstrated concurrent activation of key immune signaling pathways, including IFN signaling pathways, suggesting a potential interaction between tumor metabolic activities and immune signaling. At the level of basic science, this project aims to identify the metabolic and immunologic basis of BLCA disparities in AA patients by metabolomic analysis of the OXPHOS-GLS1 metabolic axis and by using cutting-edge single-cell RNA sequencing and imaging mass cytometry to profile the tumor immune microenvironment and analyze tumor cell-immune cell interactions. At the translational level this work will lay the foundation to test therapeutic strategies targeting complex 1 alone or in combination with GLS1 inhibitor in AA BLCA patients. If successful, these metabolic therapeutic strategies may be further combined with immunotherapeutic interventions for AA BLCA patients.

项目摘要 非裔美国人（AA）膀胱癌（BLCA）患者的生存率和肿瘤学结局较差， 他们的欧洲美国（EA）同行。我们认为，AA患者的生存率较低是由于 部分是通过改变肿瘤特异性生物活性。我们已经通过质谱分析， 转录组学和功能生物学在AA和EA BLCA患者的祖先验证的细胞系和肿瘤中 AA BLCA中存在不成比例的线粒体失调和免疫激活模式 患者基于这一认识，我们首先描述了下游代谢变化，并发现， 线粒体复合物I失调在AA BLCA患者中更常见，并与 更积极的BLCA。此外，靶向抑制复合物I导致癌症预后的改善。 临床前模型此外，我们发现含有增加的复合物I活性的AA肿瘤表现出了 通过激活GLS 1，进入TCA循环的谷氨酰胺流量增加，导致脂肪酸通过还原酶积累， 羧化作用此外，具有增加的线粒体复合物1活性的AA肿瘤表现出增强的 关键复合物I基因NDUFB 8的表达。NDUFB 8的敲低（KD）导致线粒体DNA的减少。 复合物1活性、谷氨酰胺代谢、ATP产生和BLCA生长的消退。最后，我们发现 线粒体复合物1活性增加的AA肿瘤也表现出关键蛋白的同时激活 免疫信号通路，包括IFN信号通路，表明肿瘤之间的潜在相互作用 代谢活动和免疫信号。在基础科学层面，该项目旨在确定代谢 通过OXPHOS-GLS 1代谢组学分析AA患者BLCA差异的免疫学基础 代谢轴，并通过使用最先进的单细胞RNA测序和成像质谱细胞术来分析 肿瘤免疫微环境和分析肿瘤细胞-免疫细胞相互作用。在翻译层面， 这项工作将为测试单独靶向复合物1或与GLS 1联合靶向的治疗策略奠定基础 AA BLCA患者中的抑制剂。如果成功的话，这些代谢治疗策略可以进一步与 对AA BLCA患者进行免疫干预。