Unravel a novel metabolic pathway orchestrating prostate cancer progression and therapeutic resistance

揭示协调前列腺癌进展和治疗耐药的新代谢途径

• 批准号: 10907171
• 负责人: Hui-Kuan Lin
• 金额: $ 50.64万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-03 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10907171
• 关键词: AKT Signaling Pathway; Ablation; Androgens; Automobile Driving; Back; Biochemical; Biological Assay; Cancer Etiology; Cancer Patient; Cell Maintenance; Cell Proliferation; Cell Survival; Cells; Cessation of life; Defect; Development; Drug resistance; Genetic; Goals; Human; Impairment; Inositol; Light; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metabolic; Metabolic Pathway; Mitochondria; Neoplasm Metastasis; Oncogenic; Outcome; Pathologic; Patients; Phosphotransferases; Physiological; Play; Population; Prostate; Prostate Ablation; Prostate Cancer therapy; Proteins; RNA Splicing; Regulation; Reporting; Resistance; Role; Signal Pathway; Signal Transduction; Solid; Specimen; Stem Cell Factor; Testing; United States; Validation; Variant; Xenograft Model; advanced prostate cancer; aldehyde dehydrogenases; androgen deprivation therapy; assay development; cancer drug resistance; cancer initiation; cancer stem cell; castration resistant prostate cancer; clinically relevant; clinically significant; druggable target; experimental study; genetic approach; in vivo; innovation; insight; knock-down; men; metabolomics; mouse model; new therapeutic target; novel; overexpression; patient derived xenograft model; pharmacologic; prostate cancer cell; prostate cancer progression; resistance mechanism; stem cell biomarkers; stem cell population; stemness; survival outcome; therapeutic target; therapeutically effective; therapy resistant; transcriptomics; tumor; tumor metabolism

Summary Prostate cancer is the second leading cause of cancer deaths in the United States. While androgen ablation therapy (ABT) is the mainstay of therapy for men with prostate cancer, most patients with prostate cancer will inevitably develop castration-resistant prostate cancer (CRPC), which no longer responds to ABT treatment. Thus, understanding of the mechanisms leading to CRPC and ABT resistance is urgently needed. Several mechanisms account for the occurrence of CRPC, such as activation of 3-kinase/Akt signaling pathway, which plays a critical role in cell proliferation and cell survival, and higher expression of AR and AR splicing variants, which facilitate prostate cancer cell survival under very low androgen concentrations. Of note is that prostate cancer stem cells (PCSCs) also known as cancer initiating cells (CICs), which account for a small cell population prostate cancer cells, are critically involved in the development of CRPC. But how PCSCs are regulated and how they can be pharmacologically targeted are currently not well understood. While several stem cell factors such as SOX2 playing an important role in maintaining PCSC pool and functions are identified, there is no effective strategy to block the action of these proteins in order to eradicate PCSCs within the cancer. Thus, identifying key druggable targets maintaining PCSCs could provide novel paradigms and effective strategies for prostate cancer therapy and overcoming ABT resistance. Our goal in this study is to identify a novel mechanism underlying PCSC maintenance, which could be harnessed to develop an effective strategy for CRPC targeting. Using systematic metabolomics and transcriptomics in conjunction with biochemical validation and in vivo tumor development assays, we unraveled a novel oncogenic and metabolic signaling pathway, which was elevated during ABT treatment and in advanced human prostate cancer, is critical for maintaining the stemness and pool of PCSCs and CRPC development. Of note, we observed aberrant AMPK activation and AMPK-dependent mitochondria fission upon loss of this metabolic signaling, correlated with the defect in stemness and pool of PCSCs and prostate cancer progression. In light of these findings, we hypothesized that this newly discovered metabolic signaling is crucial for restricting aberrant AMPK-dependent mitochondrial fission to maintain the pool and stemness of PCSCs, thereby leading to CRPC and ABT resistance. Our hypothesis has been formulated based on our solid and innovative preliminary results. In this proposal, we proposed three specific aims to test this paradigm-shift hypothesis. Our study has not only revolutionized and significantly advanced our understanding of cancer metabolism in PCSC regulation, but also offered a promising strategy to treat advanced prostate cancer and overcoming ABT resistance.

概括 前列腺癌是美国癌症死亡的第二大原因。而雄激素消融 治疗（ABT）是针对前列腺癌男性治疗的主要治疗，大多数前列腺癌患者将 不可避免地会出现耐cast割的前列腺癌（CRPC），不再对ABT治疗做出反应。 因此，迫切需要了解导致CRPC和ABT抗性的机制。一些 机制解释了CRPC的发生，例如3-激酶/AKT信号通路的激活， 在细胞增殖和细胞存活中起关键作用，以及AR和AR剪接变体的较高表达， 这有助于在非常低的雄激素浓度下的前列腺癌细胞存活。值得注意的是前列腺 癌症干细胞（PCSC）也称为癌细胞启动细胞（CICS），该细胞占小细胞种群 前列腺癌细胞与CRPC的发展至关重要。但是如何调节PCSC和 目前尚不清楚如何以药理为目标。而几个干细胞因素 例如SOX2在确定PCSC池和功能中起重要作用，没有 阻止这些蛋白质作用以消除癌症中的PCSC的有效策略。因此， 确定维护PCSC的关键可药物目标可以为新颖的范式和有效的策略提供 前列腺癌疗法和克服ABT耐药性。我们在这项研究中的目标是确定一种新型机制 PCSC维护的基础，可以利用这为CRPC靶向制定有效的策略。 使用系统的代谢组学和转录组学结合生化验证和体内肿瘤 开发测定法，我们解开了一种新型的致癌和代谢信号通路，该通路被升高 在ABT治疗和晚期人类前列腺癌中，对于维持茎和池至关重要 PCSC和CRPC开发。值得注意的是，我们观察到异常AMPK激活和AMPK依赖性 线粒体裂变失去了这种代谢信号传导，与茎和池的缺陷相关 PCSC和前列腺癌的进展。鉴于这些发现，我们假设这个新发现 代谢信号传导对于限制异常AMPK依赖性线粒体裂变至关重要 PCSC的干性，从而导致CRPC和ABT抗性。我们的假设已被提出 基于我们扎实和创新的初步结果。在此提案中，我们提出了三个特定目标以测试 这个范式移位假设。我们的研究不仅彻底改变了我们的 了解PCSC法规中癌症代谢的理解，但也提供了一种有希望的治疗先进的策略 前列腺癌和克服ABT耐药性。