Metabolic Rewiring Promotes AA PCa by Regulating Stromal-Epithelial Interaction

代谢重新布线通过调节间质-上皮相互作用促进 AA PCa

• 批准号: 10652987
• 负责人: Ganesh S Palapattu
• 金额: $ 37.18万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10652987
• 关键词: 6-Phosphofructo-2-kinase; Actins; Address; Adenosine; African American; African ancestry; American; Benign; Biochemical; Biochemical Markers; Bioinformatics; Biological; Biological Assay; Biological Markers; Biological Process; Biometry; CD44 gene; Cancer Biology; Cancer Patient; Carbon; Cells; Cellular Metabolic Process; Clinical; Clinical Management; Collagen; Collection; Data; Development; Diagnostic; Drug Targeting; Enzymes; Epidemiology; Epithelial-Stromal Communication; European; Foundations; Fructose; Future; Genes; Glean; Glucose; Glycolysis; In Vitro; Incidence; Inosine; Knowledge; Link; Malignant neoplasm of prostate; Mass Spectrum Analysis; Measures; Mediator; Metabolic; Metabolic Marker; Metabolism; Microarray Analysis; NADP; Operative Surgical Procedures; Organ; Pathologic; Pathology; Pathway interactions; Patients; Pentosephosphate Pathway; Phenotype; Plasma; Production; Property; Prostate; Prostatectomy; Purine Nucleotides; Race; Recurrence; Recurrent Malignant Neoplasm; Regulation; Research; Risk; Role; Route; Sampling; Science; Smooth Muscle; Stromal Cells; Techniques; Tenascin; Testing; Therapeutic; Tissue Microarray; Tissues; Training; Translating; Tumor Cell Migration; Tumor Promotion; Urine; adenosine deaminase; arm; biomarker panel; cancer health disparity; cancer recurrence; candidate identification; case control; clinical predictors; epidemiologic data; follow-up; health disparity; in vivo; insight; men; metabolome; metabolomics; novel; nucleotide metabolism; overexpression; predictive marker; prognostic; prostate cancer cell; prostate cancer cell line; prostate cancer model; small molecule; therapeutic target; tumor; tumor metabolism; tumor microenvironment; tumor progression

The long-term objective of our research plan is to reduce the disproportionate effects of prostate cancer on African American men. In this application, we have used the technique of metabolomic profiling to uncover underlying biochemical differences between prostate cancers of African American and European American origin. Metabolomics describes the science of quantifying the levels of metabolites (e.g., small molecules) that are the byproducts of cellular metabolism. That is to say, in this kind of analysis we are measuring the biochemical entities (or metabolites) that are produced by the functional machinery of the cell. With knowledge of the identity of specific metabolites we can infer the biological processes that produced them, thus gaining insight into a cell’s metabolism. Given this, a guiding principle of application is that unique biochemical differences exist between prostate cancers of African American and European American origin and that these differences can influence the tumors and their surrounding cells termed stroma such that together they can promote the progression of the tumors. Since African American prostate cancer grow and progress more rapidly than European American tumors, our studies will potentially address some of the causes underlying prostate cancer health disparity. In addition, it will also build a first-of-its-kind biomarker panel that can predict cancer recurrence in ancestry verified African American men with prostate cancer. In this proposal, we will i) identify the biochemical mechanism that drives elevated levels of inosine in African American Prostate Cancer, ii) evaluate the function of elevated inosine in making African American tumors aggressive and invoke tumor promoting properties in the surrounding stromal cells and iii) develop plasma based metabolic markers for biochemical recurrence in African American men. At the conclusion of this study, we will have developed a racially derived metabolomic model for prostate cancer as well as identified candidate pathways for future drug targeting. We would have also built a proof-of-principle metabolite-based test with the ability to predict cancer recurrence based on the ancestry of the patient. In the longer term, this test will be validated and translated into a clinical assay that should have the ability to predict the recurrence of prostate cancer in an ancestry informed fashion in prostate cancer patients.

我们研究计划的长期目标是减少前列腺癌对健康的不成比例的影响。 非裔美国人。在这一应用中，我们使用了代谢组谱技术来揭示 非裔美国人和欧洲裔美国人前列腺癌的潜在生化差异 起源。代谢组学描述了对代谢产物(例如，小分子)水平进行量化的科学 是细胞代谢的副产品。也就是说，在这种分析中，我们测量的是 由细胞的功能机械产生的生化实体(或代谢物)。带着知识 对于特定代谢物的特性，我们可以推断产生它们的生物过程，从而获得 洞察细胞的新陈代谢。鉴于此，应用的指导原则是独特的生化 起源于非裔美国人和欧洲裔美国人的前列腺癌之间存在差异，这些 差异可以影响肿瘤及其周围称为间质的细胞，因此它们共同可以 促进肿瘤的发展。由于非裔美国人前列腺癌的生长和进展更多 我们的研究比欧美人的肿瘤更快，可能会解决一些潜在的原因 前列腺癌的健康差距。此外，它还将建立首个此类生物标志物小组，可以预测 祖先的癌症复发证实了患有前列腺癌的非裔美国人男性。在本提案中，我们将i) 确定导致非裔美国人前列腺癌肌苷水平升高的生化机制， 二)评估肌苷升高在使非裔美国人肿瘤侵袭和引发肿瘤方面的作用 促进周围基质细胞的特性和iii)开发基于血浆的代谢标记物 非裔美国人男性的生化复发。在这项研究结束时，我们将开发出一种 前列腺癌的种族代谢组模型以及未来药物的确定候选途径 瞄准目标。我们还将建立一种基于代谢物的原理验证测试，能够预测癌症 复发取决于患者的血统。从长远来看，这项测试将得到验证和翻译 变成了一种临床检测方法，应该能够预测前列腺癌家族中的复发 前列腺癌患者的知情时尚。

项目成果

Repair-Assisted Damage Detection Reveals Biological Disparities in Prostate Cancer between African Americans and European Americans.

维修辅助损伤检测揭示了非裔美国人和欧洲人之间前列腺癌的生物学差异。

• DOI: 10.3390/cancers14041012
• 发表时间: 2022-02-17
• 期刊: Cancers
• 影响因子: 5.2
• 作者: Krieger KL;Gohlke JH;Lee KJ;Piyarathna DWB;Castro PD;Jones JA;Ittmann MM;Gassman NR;Sreekumar A
• 通讯作者: Sreekumar A