Spatiotemporal mechanisms of eIF5A1/2-mediated metastasis in triple-negative breast cancer

eIF5A1/2介导的三阴性乳腺癌转移的时空机制

• 批准号: 10545794
• 负责人: Jonathan Kelber
• 金额: $ 1.28万
• 依托单位: CALIFORNIA STATE UNIVERSITY NORTHRIDGE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-13 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10545794
• 关键词: 3-Dimensional; Adhesions; Affect; Anti-Inflammatory Agents; Biochemistry; Biological Assay; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Breast cancer metastasis; Cancer Biology; Cancer Prognosis; Cell Cycle Kinetics; Cells; Cellular biology; Chemotherapy-Oncologic Procedure; Clinical; Complex; Data; Eukaryotic Initiation Factors; Fibronectins; Flow Cytometry; Funding; Goals; Heterogeneity; Human; Immunofluorescence Immunologic; Inflammatory; Integrins; Intervention; Knowledge; LCN2 gene; Laboratories; Mediating; Methods; Modeling; Molecular; Neoplasm Metastasis; Oncology; Outcome; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Periodicity; Pharmacology; Phosphotransferases; Pre-Clinical Model; Primary Neoplasm; Proteins; Publishing; Reporting; Research; Signal Transduction; Site; Solid Neoplasm; Testing; Tissues; Transforming Growth Factor beta; Tumor Expansion; Up-Regulation; Work; aggressive breast cancer; breast cancer progression; cancer cell; cancer subtypes; cancer type; complex IV; genetic manipulation; improved; in vivo; innovation; mortality; mouse model; neoplastic cell; novel; novel therapeutic intervention; novel therapeutics; nucleocytoplasmic transport; pre-clinical; public health relevance; response; screening; spatiotemporal; targeted treatment; treatment strategy; triple-negative invasive breast carcinoma; tumor; tumor progression; tumorigenesis

PROJECT SUMMARY Metastasis is the leading cause of mortality in patients with solid tumors. Since there are no clinically- approved targeted therapies for treating triple-negative breast cancer (TNBC), metastatic TNBC pre- sents a dire clinical situation for which intervention strategies are urgently needed. The long-term goal of this proposal is to elucidate novel tumor cell autonomous and non-autonomous mechanisms that drive TNBC progression and metastasis. The overall objective of this proposal is to define the molecu- lar/cellular basis by which post-translational hypusination and nucleocytoplasmic transport of eukaryotic initiation factor 5A (eIF5A1/2) governs pseudopodium-enriched atypical kinase one (PEAK1)-dependent invasion/dissemination and lipocalin two (LCN2)-mediated reprogramming of the premetastatic niche (PMN). Toward this end, evidence is presented that the eIF5A1/2 hypusination/activation pathway associates with poor TNBC prognosis and is required for TGFβ/PEAK1-driven metastasis and LCN2 expression in TNBC cells. Furthermore, the eIF5A1/2-LCN2 axis is identified as a novel mechanism through which primary tumor cells remodel the PMN to support TNBC cell expansion. Thus, the central hypothesis of this proposal is that hypusination and cytoplasmic localization of eIF5A1/2 in TNBC cells drives PEAK1-dependent TGFβ/fibronectin signaling crosstalk and LCN2-mediated anti-inflammatory reprogramming of the premetastatic niche to support metastasis. The approach is innovative because it represents a substantive departure from the status quo by elucidating targetable eIF5A1/2-dependent translational mechanisms of cell state plasticity at early and late stages in the metastatic cascade using the single-cell Cyclic ImmunoFluorescence (CycIF) platform, our novel in vivo/ex vivo tumor cell-free PMN reprogramming assay, the Multifunctional Approach to Pharmacological Screening (MAPS) platform and a suite of preclinical mouse models that faithfully recapitulate complementary aspects of human TNBC metastasis and progression. Furthermore, the proposed research is significant because it will define spatiotemporal mechanisms by which dysregulation of eIF5A1/2 expression, hypusination and subcellular localization drive TNBC pathogenesis and identify targeted treatment strategies for metastatic TNBC. Specific Aim 1 will determine cancer cell autonomous mechanisms of eIF5A1/2- mediated TNBC cell invasion and dissemination. Specific Aim 2 will identify eIF5A1/2-dependent mechanisms of premetastatic niche reprogramming that support TNBC cell seeding and expansion. The collective knowledge gained from these studies will elucidate targetable mechanisms that govern both early and late stages of TNBC metastasis and establish rationale for new therapeutic combina- tions to overcome TNBC progression and improve patient outcomes.

项目摘要 转移是实体瘤患者死亡率的主要原因。由于没有临床 批准治疗三阴性乳腺癌（TNBC），转移性TNBC的靶向疗法 发送直接需要干预策略的直接临床情况。长期目标 该建议的是阐明新型的肿瘤细胞自主和非自主机制， 驱动TNBC的进展和转移。该提议的总体目的是定义分子 LAR/细胞基础，将真核生物的翻译后非偶然和核细胞胞质转运 启动因子5a（EIF5A1/2）控制富含假性的非典型激酶ONE（峰1）依赖性 入侵/传播和Lipocalin两（LCN2）介导的前转移生态位的重编程 （PMN）。为此，有证据表明EIF5A1/2非偶然/激活途径 与TNBC预后较差的关联，是TGFβ/Peak1驱动的转移和LCN2所必需的 TNBC细胞中的表达。此外，EIF5A1/2-LCN2轴被确定为一种新机制 原发性肿瘤细胞重塑PMN以支持TNBC细胞膨胀。那，中央 该提议的假设是eIF5A1/2在TNBC细胞中的降低和细胞质定位 驱动依赖于峰值的TGFβ/纤连蛋白信号传导串扰和LCN2介导的抗炎 重新编程前转移的细分市场以支持转移。这种方法是创新的，因为它 通过阐明可定位的EIF5A1/2依赖性，代表与现状的实质性不同 在转移级联的早期和晚期的细胞状态可塑性的翻译机制使用 单细胞环境免疫荧光（CYCIF）平台，我们的新型体内/Ex Vivo肿瘤细胞无 PMN重编程测定，多功能药理学筛选方法（地图） 平台和一套临床前鼠标模型，忠实地概括了互补方面 人类TNBC转移和进展。此外，拟议的研究很重要，因为它 将定义时空机制，通过该机制，EIF5A1/2表达失调，降低 和亚细胞定位驱动TNBC发病机理，并确定针对的治疗策略 转移性TNBC。具体目标1将确定eIF5A1/2-的癌细胞自主机制 介导的TNBC细胞侵袭和传播。特定目标2将识别eif5a1/2依赖性 支撑TNBC细胞播种和膨胀的前转移性利基重编程的机制。 从这些研究中获得的集体知识将阐明管理的目标机制 TNBC转移的早期和晚期和新治疗组合的建立基本原理 克服TNBC进展并改善患者预后的情况。