Chemical Genetic Dissection of Aurora A in Promoting EMT and Stem Cells Phenotype

Aurora A 促进 EMT 和干细胞表型的化学遗传学解析

• 批准号: 8504422
• 负责人: Kavita Shah
• 金额: $ 7.7万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8504422
• 关键词: Adverse effects; Apoptosis; Biological Markers; Cancer Patient; Cell Cycle; Cell Death; Cells; Clinical; Clinical Trials; Data; Development; Diagnosis; Diagnostic; Diffuse; Disease Management; Dissection; Dose; Drug Targeting; Drug resistance; Effectiveness; Enzymes; Epithelial Cells; Exhibits; Feedback; G2 Phase; Genetic Screening; Goals; Human; Light; Link; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mitosis; Mitotic; Molecular; Neoplasm Metastasis; Normal Cell; Nuclear; Nuclear Proteins; Oncogenic; Oncologist; Outcome; Pancreas; Pathway interactions; Phase; Phase II Clinical Trials; Phenotype; Phosphorylation; Plant Roots; Play; Prognostic Marker; Property; Proteins; Radiation therapy; Recurrence; Refractory; Research; Resistance; Role; Sampling; Signal Transduction; Solid Neoplasm; Stem cells; Taxane Compound; Testing; Tissues; Toxic effect; Treatment Efficacy; Tumorigenicity; Up-Regulation; Validation; Work; aurora-A kinase; base; cancer cell; cancer stem cell; cell type; chemical genetics; chemotherapeutic agent; effective therapy; epithelial to mesenchymal transition; human STK6 protein; in vivo; inhibitor/antagonist; innovation; novel; overexpression; pancreatic cancer cells; pancreatic neoplasm; prevent; prognostic; public health relevance; response; self-renewal; taxane; therapeutic target; tool; transcription factor; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Pancreatic cancer (PC) is extremely lethal. Early metastasis prior to diagnosis, tumor recurrence and resistance towards current chemo-radiation therapies are common among PC patients. Recent evidence indicates that the acquisition of epithelial-to-mesenchymal transition (EMT) and induction of cancer stem cell (CSC) phenotypes in PC tumors are important underlying causes for these occurrences. However, the mechanisms leading to EMT and CSC phenotypes remain unclear. This information is critical for the discovery of novel targeted therapies for the treatment of PC that offer superior outcome. The long term goal is to identify therapeutically effective drug targets in PC. Our recent unpublished data have uncovered a critical role of Aurora A (AA) kinase in promoting EMT and CSC in PC. AA is upregulated in PC and contributes significantly to tumorigenesis and metastasis; however, the molecular mechanisms remain unknown. Using an innovative chemical genetic screen, FOXM1 transcription factor was identified as a direct target of AA in highly malignant AsPC1 cells. AA directly phosphorylates FOXM1 at S361 stabilizing its levels. In turn, FOXM1 also stabilizes AA levels, thereby triggering a reciprocal positive feedback loop. FOXM1 upregulation is known to promote EMT and CSC phenotypes in PC cells. The objective in this proposal is to determine the contribution of FOXM1 as a critical effector of AA by which it promotes EMT and CSC phenotype in PC tumors. The central hypothesis is that AA and FOXM1 are potential drug targets which promote aggressive oncogenic pathways in PC synergistically. This hypothesis will be tested by pursuing three specific aims: 1) Determine a potential role of AA in promoting EMT and CSC in PC cells. 2) Determine the consequences of AA-mediated phosphorylation of FOXM1 on various oncogenic pathways in PC cells. 3) Determine AA and FOXM1 levels in tandem in human clinical samples and their correlation with clinical outcomes. The approach is innovative because the central hypothesis was formulated based on a novel AA substrate, FOXM1, discovered using a powerful chemical genetic approach. No cancer-specific substrate of AA has been identified in PC. AA has not been linked to CSC or EMT to date. Furthermore, FOXM1 or AA levels have not been analyzed in tandem in human PC tissues. The proposed research is significant because validation of FOXM1 as an AA substrate will provide a potent tool to inhibit FOXM1 deregulation in metastatic PC. Correlation of AA and FOXM1 levels with divergent clinical outcomes are expected to reveal potential prognostic and diagnostic biomarkers for PC. The positive impact of our work will be the validation of AA as a potential drug target for treating/preventing EMT, CSC and chemoresistance, either alone or in combination with FOXM1 inhibitors.

描述（由申请人提供）：胰腺癌（PC）极其致命。诊断前的早期转移、肿瘤复发和对当前化疗放疗的耐药性在 PC 患者中很常见。最近的证据表明，PC 肿瘤中上皮间质转化 (EMT) 的获得和癌症干细胞 (CSC) 表型的诱导是这些发生的重要根本原因。然而，导致 EMT 和 CSC 表型的机制仍不清楚。这些信息对于发现治疗 PC 并提供卓越疗效的新型靶向疗法至关重要。长期目标是确定 PC 中治疗有效的药物靶点。我们最近未发表的数据揭示了 Aurora A (AA) 激酶在促进 PC 中 EMT 和 CSC 中的关键作用。 AA 在 PC 中表达上调，对肿瘤发生和转移有显着贡献；然而，其分子机制仍不清楚。使用创新的化学遗传筛选，FOXM1 转录因子被确定为高度恶性 AsPC1 细胞中 AA 的直接靶标。 AA 直接磷酸化 FOXM1 的 S361，稳定其水平。反过来，FOXM1 也能稳定 AA 水平，从而触发相互正反馈循环。 FOXM1 上调已知可促进 PC 细胞中的 EMT 和 CSC 表型。本提案的目的是确定 FOXM1 作为 AA 的关键效应子的贡献，通过它促进 PC 肿瘤中的 EMT 和 CSC 表型。中心假设是 AA 和 FOXM1 是潜在的药物靶点，可协同促进 PC 中的侵袭性致癌途径。该假设将通过追求三个具体目标来检验：1) 确定 AA 在促进 PC 细胞 EMT 和 CSC 中的潜在作用。 2) 确定 AA 介导的 FOXM1 磷酸化对 PC 细胞中各种致癌途径的影响。 3) 确定人类临床样本中的 AA 和 FOXM1 水平及其与临床结果的相关性。该方法具有创新性，因为中心假设是基于使用强大的化学遗传学方法发现的新型 AA 底物 FOXM1 制定的。在 PC 中尚未发现 AA 的癌症特异性底物。迄今为止，AA 尚未与 CSC 或 EMT 关联。此外，尚未对人类 PC 组织中的 FOXM1 或 AA 水平进行串联分析。拟议的研究意义重大，因为验证 FOXM1 作为 AA 底物将提供抑制转移性 PC 中 FOXM1 失调的有效工具。 AA 和 FOXM1 水平与不同临床结果的相关性有望揭示 PC 的潜在预后和诊断生物标志物。我们工作的积极影响将是验证 AA 作为单独或与 FOXM1 抑制剂联合治疗/预防 EMT、CSC 和化疗耐药的潜在药物靶点。