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: 10374340
• 负责人: Hui-Kuan Lin
• 金额: $ 49.74万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 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 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10374340
• 关键词: AKT Signaling Pathway; Ablation; Androgens; Automobile Driving; Back; Biochemical; Biochemical Genetics; 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; Lead; Light; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metabolic; Metabolic Pathway; Mitochondria; Neoplasm Metastasis; Oncogenic; Outcome; Pathologic; Patients; Pharmacology; 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; Therapeutic; United States; Validation; Variant; Xenograft Model; advanced prostate cancer; aldehyde dehydrogenases; androgen deprivation therapy; assay development; base; cancer drug resistance; 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; prostate cancer cell; prostate cancer progression; resistance mechanism; stem cell biomarkers; stem cell population; stemness; survival outcome; therapeutic target; 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。雄激素消融的同时 治疗（ABT）是男性前列腺癌的主要治疗方法，大多数前列腺癌患者会 不可避免地会发展为去势抵抗性前列腺癌 (CRPC)，这种癌症不再对 ABT 治疗产生反应。 因此，迫切需要了解导致 CRPC 和 ABT 耐药的机制。一些 导致 CRPC 发生的机制，例如 3-激酶/Akt 信号通路的激活， 在细胞增殖和细胞存活以及 AR 和 AR 剪接变体的较高表达中发挥关键作用， 这有助于前列腺癌细胞在极低雄激素浓度下存活。值得注意的是前列腺 癌症干细胞 (PCSC) 也称为癌症起始细胞 (CIC)，细胞群较少 前列腺癌细胞在 CRPC 的发展中发挥着重要作用。但 PCSC 是如何监管和 目前尚不清楚如何对它们进行药理学靶向。虽然有几种干细胞因子 例如 SOX2 在维持 PCSC 池中发挥重要作用并且功能被确定，没有 阻断这些蛋白质的作用以根除癌症内 PCSC 的有效策略。因此， 确定维持 PCSC 的关键药物靶点可以为治疗提供新的范例和有效的策略 前列腺癌治疗和克服 ABT 耐药性。我们这项研究的目标是确定一种新机制 潜在的 PCSC 维护，可用于制定针对 CRPC 目标的有效策略。 将系统代谢组学和转录组学与生化验证和体内肿瘤相结合 通过开发分析，我们揭示了一种新的致癌和代谢信号通路，该通路被升高 在 ABT 治疗期间和晚期人类前列腺癌中，对于维持干性和池性至关重要 PCSC 和 CRPC 开发。值得注意的是，我们观察到异常的 AMPK 激活和 AMPK 依赖性 失去这种代谢信号后线粒体分裂，与干细胞和细胞库的缺陷相关 PCSC 和前列腺癌进展。根据这些发现，我们假设这一新发现 代谢信号对于限制异常 AMPK 依赖性线粒体裂变以维持池至关重要 PCSC 的干性，从而导致 CRPC 和 ABT 耐药。我们的假设已经成立 基于我们扎实且创新的初步成果。在这个提案中，我们提出了三个具体目标来测试 这种范式转变假设。我们的研究不仅彻底改变了我们的研究，而且显着推进了我们的研究 了解 PCSC 调节中的癌症代谢，同时也提供了治疗晚期癌症的有前景的策略 前列腺癌和克服 ABT 耐药性。