The origins of metabolic reprogramming in prostate cancer

前列腺癌代谢重编程的起源

• 批准号: 10452633
• 负责人: Andrew S Goldstein
• 金额: $ 27.62万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-02 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10452633
• 关键词: Address; Androgen Antagonists; Androgen Receptor; Basal Cell; Biological Assay; Cancer Etiology; Cell Survival; Cells; Cellular Metabolic Process; Cessation of life; Data; Disease; Disease Progression; Enzymes; Epithelial; Epithelial Cells; Exhibits; Future; Genetically Engineered Mouse; Glucose; Glutaminase; Glutamine; Human; Ions; Isotope Labeling; Lead; Malignant Neoplasms; Malignant neoplasm of prostate; Mass Chromatography; Mass Spectrum Analysis; Metabolic; Metabolic Pathway; Metabolism; Molecular; Mus; Mutation; Nutrient; Oncogenes; Oncogenic; Organoids; Pathogenesis; Pharmaceutical Preparations; Phenotype; Predisposition; Prostate; Prostatic Neoplasms; Receptor Signaling; Regulation; Research; Resistance; Role; System; Therapeutic; Tissues; United States; age related; castration resistant prostate cancer; cell type; combat; experimental study; hormone therapy; human tissue; in vivo; innovation; insight; interest; men; metabolic phenotype; metabolic profile; new therapeutic target; novel; novel strategies; novel therapeutic intervention; nutrient deprivation; prostate cancer cell; prostate cancer model; prostate cancer progression; prostate carcinogenesis; response; small molecule inhibitor; targeted treatment; therapeutic target; tumor; tumor metabolism; tumorigenesis; young adult

PROJECT SUMMARY Approximately 29,000 men in the United States were estimated to die from prostate cancer in 2018. As our current therapies are not working for a large number of men with metastatic castration-resistant prostate cancer, we need innovative strategies to identify new therapeutic approaches. Advances in dissecting mechanisms of metabolic reprogramming in several tumor types has led to widespread interest in drugging metabolic vulnerabilities as a therapeutic strategy for cancer. Defining the factors that regulate metabolic reprogramming in prostate cancer is fundamental to understanding prostate cancer pathogenesis and likely to yield therapeutic targets for this lethal disease. Two key factors that regulate metabolic reprogramming in cancer and inform metabolic vulnerabilities that can be targeted for therapy are the disease-initiating oncogenes and the tissue or cells-of-origin. However, it is not well understood how the cells-of-origin for prostate cancer cooperate with oncogenes to reprogram metabolism. Using genetically engineered mouse models and human transformation assays, we and others have demonstrated that both prostate basal and luminal cells can serve as target cells for prostate transformation. Genetically altered basal cells must differentiate into luminal cells in order to initiate cancer, establishing a key role for differentiation in basal cell-initiated tumorigenesis. In response to hormonal therapy, luminal-like prostate cancer cells undergo lineage plasticity and exhibit basal cell features, demonstrating a role for differentiation in disease progression and therapy-resistance. Surprisingly, little is known about (1) metabolic activity in distinct epithelial cells of the prostate, (2) how changes in metabolism regulate epithelial differentiation, and (3) how oncogenic transformation reprograms prostate epithelial metabolism. Understanding prostate cancer metabolism requires first understanding prostate epithelial metabolism. However, such data on the metabolism of primary cell-types does not yet exist. In this proposal, mouse and human tissue will be studied in parallel to determine the extent to which the cells-of-origin and the disease-initiating oncogenes regulate metabolic reprogramming in prostate cancer. In Aim 1, we will establish metabolic signatures of distinct cells-of-origin for prostate cancer (basal and luminal). In Aim 2, we will evaluate metabolic regulation of luminal differentiation, a requirement for prostate tumorigenesis. In Aim 3, we will determine how epithelial metabolism is reprogrammed in response to genetic alterations. This novel approach will enhance our fundamental understanding of prostate tumorigenesis and may lead to new therapeutic strategies to combat lethal prostate cancer.

项目概要 2018 年，美国估计约有 29,000 名男性死于前列腺癌。 目前的疗法对大量患有转移性去势抵抗性前列腺癌的男性不起作用， 我们需要创新策略来确定新的治疗方法。解剖机制的进展 几种肿瘤类型中的代谢重编程引起了对代谢药物的广泛兴趣 作为癌症治疗策略的弱点。定义调节代谢重编程的因素 前列腺癌的研究是了解前列腺癌发病机制的基础，并可能产生治疗效果 这种致命疾病的目标。调节癌症代谢重编程并提供信息的两个关键因素 可以作为治疗目标的代谢脆弱性是疾病引发的癌基因和组织或 起源细胞。然而，目前尚不清楚前列腺癌的起源细胞如何与 癌基因重新编程新陈代谢。使用基因工程小鼠模型和人类转化 我们和其他人已经证明前列腺基底细胞和管腔细胞都可以作为靶细胞 用于前列腺转化。基因改变的基底细胞必须分化为管腔细胞才能启动 癌症，确定分化在基底细胞引发的肿瘤发生中的关键作用。响应荷尔蒙 治疗时，管腔样前列腺癌细胞经历谱系可塑性并表现出基底细胞特征， 证明分化在疾病进展和治疗抵抗中的作用。令人惊讶的是，鲜为人知 关于 (1) 前列腺不同上皮细胞的代谢活动，(2) 代谢变化如何调节 上皮分化，以及（3）致癌转化如何重新编程前列腺上皮代谢。 了解前列腺癌代谢首先需要了解前列腺上皮代谢。然而， 有关原代细胞类型代谢的此类数据尚不存在。在该提案中，小鼠和人体组织 将并行研究以确定起源细胞和疾病引发癌基因的程度 调节前列腺癌的代谢重编程。在目标 1 中，我们将建立不同的代谢特征 前列腺癌的起源细胞（基底癌和管腔癌）。在目标 2 中，我们将评估管腔的代谢调节 分化，是前列腺肿瘤发生的必要条件。在目标 3 中，我们将确定上皮代谢如何 被重新编程以响应基因改变。这种新颖的方法将增强我们的基础 了解前列腺肿瘤的发生，可能会产生新的治疗策略来对抗致命的前列腺 癌症。