Defining the role of microenvironmental ammonia in colorectal cancers

定义微环境氨在结直肠癌中的作用

• 批准号: 10463578
• 负责人: Hannah Noelle Bell
• 金额: $ 0.62万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2022-08-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10463578
• 关键词: APC mutation; Advanced Development; Advanced Malignant Neoplasm; Ammonia; Antitumor Response; Attenuated; Automobile Driving; Bioenergetics; Carcinoma; Cell Proliferation; Cell physiology; Cells; Chemicals; Clinic; Clinical; Colon; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; Colorectal Neoplasms; Data; Data Analyses; Diagnosis; Drug Metabolic Detoxication; Dysplasia; Effectiveness; Epithelial; Epithelial Cells; Gases; Gene Expression; Genetic; Genetic Transcription; Genotype; Goals; Growth; Hepatic; Hyperammonemia; Immune; Immune Evasion; Immune response; Immunotherapeutic agent; Immunotherapy; In Vitro; Incidence; Institution; Intervention; K-ras mouse model; KRAS2 gene; KRASG12D; Laboratories; Malignant Neoplasms; Mentors; Metabolic; Metabolism; Metastatic Neoplasm to the Liver; Metastatic Neoplasm to the Lung; Modeling; Multiomic Data; Mus; Mutation; Neoplasm Metastasis; Nuclear; Nude Mice; Oncology; Organ; Ornithine; Patients; Physicians; Physiological; Process; Proteomics; Public Health; RNA analysis; Regimen; Regulation; Resistance; Role; Scientist; Signal Transduction; Specific qualifier value; Supplementation; Survival Rate; T cell response; T-Cell Proliferation; T-Lymphocyte; TP53 gene; Tamoxifen; Testing; Training; Tumor-Derived; Tumor-infiltrating immune cells; Urea; Waste Products; Work; adenoma; aminoacid biosynthesis; anti-tumor immune response; base; cancer cell; cancer diagnosis; carcinogenesis; career; cell growth; cell type; colon cancer cell line; colon cancer patients; colon carcinogenesis; cytokine; driver mutation; immune checkpoint blockers; improved; metabolomics; mortality; mouse model; multiple omics; mutant; neoplastic cell; prevent; promoter; response; transcriptional reprogramming; transcriptome sequencing; transcriptomics; treatment response; tumor; tumor growth; tumor microenvironment; tumor progression; tumor-immune system interactions; urea cycle; wasting

Abstract: Colorectal cancer is a grave public health concern with only a 14% survival rate for Stage IV diagnosis, and few viable treatment options. Colon tumors are composed of a cadre of cells and the interplay between these cells is critical for tumor growth. Previous work shows that the initial immune-tumor dynamic is robustly anti- tumor, but that this anti-tumor response is attenuated as tumors progress. Immunotherapies that re-activate the anti-tumor response are currently widely used in many cancers. Although colon tumors have a robust immune infiltrate, immunotherapies have largely failed for unclear reasons. Further, cancer cells are known to reprogram cellular metabolism to meet their proliferative needs. Cancer cell proliferation produces metabolic waste products that can be re-purposed to maintain cellular bioenergetic needs. However, it is clear that the vast majority of the metabolic byproducts accumulate in the tumor microenvironment. There is a critical gap regarding how metabolic waste products interact with the immune infiltrates. My preliminary data demonstrates that KRAS mutant colon tumors have an increase in ammonia waste that accumulates in the tumor microenvironment. Moreover, my preliminary data shows that T cell proliferation and anti-tumor response is significantly inhibited at biologically relevant concentrations that have been detected in colon tumors, while other cell types are largely unaffected. I have also shown that chemical ammonia detoxification reduces tumor growth in a T cell dependent manner. This suggests that ammonia waste contributes to the attenuated anti- tumor immune response commonly observed in colon cancer. data I hypothesize that increased microenvironmental ammonia in advanced cancers is central to maintaining an immunosuppressive state by altering T cell function. The long-term goal of this proposal is to understand how colorectal tumors modulate the microenvironment through metabolic products to decrease the effectiveness of the immune response. Understanding this will advance the development of immune-based therapeutic regimens. Based on these observations, the experimental focus of this proposal is on the regulatory role of tumor-generated ammonia on T cell function. Aim 1 will determine whether KRAS mutation is driving ammonia accumulation in advanced cancers. Aim 2 will explore how detoxifying ammonia in the tumor microenvironment increases the T cell immune response, using both genetic and chemical interventions. Preventing this negative hetero- cellular cross talk between the tumor and T cells may improve the efficacy of immunotherapy approaches in colorectal cancer. Importantly, pursuing the aims specified in this proposal will provide rigorous scientific and clinical training at a highly ranked and well supported institution. This type of institutional, facility, and mentor support will further my path towards a career as a physician scientist with an active oncology laboratory.

抽象的： 结直肠癌是一个严重的公共卫生问题，IV 期诊断的生存率仅为 14%，并且 可行的治疗方案很少。结肠肿瘤由一群细胞组成，这些细胞之间相互作用 细胞对于肿瘤生长至关重要。先前的工作表明，最初的免疫肿瘤动态是强有力的抗 肿瘤，但这种抗肿瘤反应随着肿瘤的进展而减弱。重新激活的免疫疗法 抗肿瘤反应目前广泛应用于多种癌症。尽管结肠肿瘤具有很强的 由于免疫渗透，免疫疗法基本上因不明原因而失败。此外，已知癌细胞 重新编程细胞代谢以满足其增殖需求。癌细胞增殖产生代谢 可以重新利用的废物来维持细胞生物能量的需求。然而，很明显的是， 绝大多数代谢副产物积聚在肿瘤微环境中。存在关键差距 关于代谢废物如何与免疫浸润相互作用。我的初步数据表明 KRAS 突变结肠肿瘤中积累的氨废物增加 微环境。此外，我的初步数据显示，T 细胞增殖和抗肿瘤反应是 在结肠肿瘤中检测到的生物学相关浓度下显着抑制，同时 其他细胞类型基本上不受影响。我还表明化学氨解毒可以减少肿瘤 以 T 细胞依赖性方式生长。这表明氨废物有助于减弱抗 结肠癌中常见的肿瘤免疫反应。我假设增加的数据 晚期癌症中微环境氨对于维持免疫抑制至关重要 通过改变T细胞功能来改变状态。该提案的长期目标是了解结直肠肿瘤如何 通过代谢产物调节微环境，降低免疫效果 回复。了解这一点将促进基于免疫的治疗方案的开发。基于 根据这些观察结果，本提案的实验重点是肿瘤生成的调节作用 氨对 T 细胞功能的影响。目标 1 将确定 KRAS 突变是否导致氨积累 晚期癌症。目标 2 将探索肿瘤微环境中的氨解毒如何增加 T 细胞免疫反应，利用遗传和化学干预。防止这种负面的异质性 肿瘤和 T 细胞之间的细胞串扰可能会提高免疫治疗方法的疗效 结直肠癌。重要的是，追求本提案中指定的目标将提供严格的科学和 在排名靠前且支持良好的机构进行临床培训。这种类型的机构、设施和导师 支持将进一步推动我成为一名拥有活跃的肿瘤学实验室的医师科学家的职业生涯。

项目成果

"PROBE"ing the Role of Cytoreductive Nephrectomy in Advanced Renal Cancer.

“探索”减瘤性肾切除术在晚期肾癌中的作用。

• 发表时间: 2022-03-15
• 作者: Bell, Hannah;Cotta, Brittney H;Salami, Simpa S;Kim, Hyung;Vaishampayan, Ulka
• 通讯作者: Vaishampayan, Ulka