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

项目摘要 与非裔美国人(AA)膀胱癌(BLCA)患者相比，患者的生存率和肿瘤预后较差 给他们的欧洲美洲(EA)同行。我们认为，再生障碍性贫血患者的低存活率是 部分是由于肿瘤特异性生物活性的改变。我们已经通过质谱学在全基因组范围内确定 AA和EA BLCA患者祖先验证的细胞系和肿瘤的转录和功能生物学 再障BLCA患者存在不成比例的线粒体失调和免疫激活模式 病人。基于这一认识，我们首先描述了下游代谢的变化，并发现 线粒体复合体I异常在AA BLCA患者中更常见，并与 更具侵略性的BLCA。此外，靶向抑制复合体I导致改善癌症预后。 临床前模型。此外，我们发现，含有增加的复合体i活性的AA肿瘤表现出 更高的谷氨酰胺流量通过激活GLS1进入TCA循环，导致脂肪酸通过还原积累 羧化作用。此外，线粒体复合体1活性增加的AA肿瘤表现为增强 关键复合体I基因NDUFB8的表达。NDUFB8基因敲除(KD)导致线粒体减少 复合体1的活性，谷氨酰胺代谢，三磷酸腺苷的产生，以及BLCA生长的倒退。最后，我们发现 线粒体复合体1活性增加的AA肿瘤也显示Key同时激活 免疫信号通路，包括干扰素信号通路，提示肿瘤之间可能存在相互作用 代谢活动和免疫信号。在基础科学的层面上，这个项目的目的是确定新陈代谢 通过OXPHOS-GLS1代谢组学分析探讨再生障碍性贫血患者BLCA差异的免疫学基础 代谢轴，并通过使用尖端的单细胞RNA测序和成像质量细胞术来描述 肿瘤免疫微环境，分析肿瘤细胞与免疫细胞的相互作用。在翻译层面上，这是 这项工作将为测试单独针对复合体1或与GLS1联合使用的治疗策略奠定基础 AA、BLCA患者体内的抑制物。如果成功，这些代谢治疗策略可能会进一步与 AA BLCA患者的免疫治疗干预。

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.