The origins of metabolic reprogramming in prostate cancer

项目总结 据估计，2018年美国约有2.9万名男性死于前列腺癌。作为我们的 目前的治疗方法对大量患有转移性去势抵抗前列腺癌的男性无效， 我们需要创新的战略来确定新的治疗方法。牙周炎的解剖机制研究进展 几种肿瘤类型的代谢重新编程引起了人们对新陈代谢药物的广泛兴趣 将脆弱性作为癌症的治疗策略。确定调节新陈代谢重新编程的因素 前列腺癌的发病机制是理解前列腺癌发病机制的基础，并有可能产生治疗作用 这种致命疾病的目标。调节癌症代谢重编程的两个关键因素和信息 可作为治疗靶点的代谢脆弱性是引发疾病的癌基因和组织或 来源细胞。然而，前列腺癌的起源细胞如何协同作用尚不清楚。 癌基因对新陈代谢进行重新编程。利用基因工程小鼠模型和人类转化 通过分析，我们和其他人证明了前列腺基底细胞和腔细胞都可以作为靶细胞。 用于前列腺癌的治疗。基因改变的基底细胞必须分化为腔细胞才能启动 癌症，在基底细胞启动的肿瘤发生中确立分化的关键作用。对荷尔蒙的反应 治疗后，管腔样前列腺癌细胞经历传代可塑性并表现出基本细胞特征， 显示了分化在疾病进展和治疗耐药中的作用。令人惊讶的是，鲜为人知的是 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。 了解前列腺癌的新陈代谢需要首先了解前列腺上皮的新陈代谢。然而， 关于初级细胞类型新陈代谢的数据尚不存在。在这项提案中，老鼠和人类组织 将同时进行研究，以确定起源细胞和致病癌基因的程度 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(基底细胞和腔细胞)。在目标2中，我们将评估鲁米那的代谢调节。 分化，这是前列腺癌发生的必要条件。在目标3中，我们将确定上皮新陈代谢如何 被重新编程以回应基因的改变。这种新颖的方法将加强我们的根本 了解前列腺癌的发生并可能导致对抗致死性前列腺癌的新的治疗策略 癌症。

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.