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: 10613025
• 负责人: Jonathan Kelber
• 金额: $ 4.32万
• 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/10613025
• 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的主要原因。因为临床上没有- 用于治疗三阴性乳腺癌（TNBC）、转移性TNBC前 因此，迫切需要采取干预措施。远景目标 该建议的目的是阐明新的肿瘤细胞自主和非自主机制， 驱动TNBC进展和转移。该提案的总体目标是定义分子- 真核生物蛋白质翻译后羟腐胺酸化和核质转运 起始因子5A（eIF 5A 1/2）控制伪足富集非典型激酶1（PEAK 1）依赖性 侵袭/播散和脂质运载蛋白2（LCN 2）介导的转移前小生境重编程 （PMN）。为此，有证据表明eIF 5A 1/2 hypusination/激活途径 与TNBC预后不良相关，并且是TGFβ/PEAK 1驱动的转移和LCN 2所必需的。 在TNBC细胞中的表达。此外，eIF 5A 1/2-LCN 2轴被确定为新的机制 通过该过程，原发性肿瘤细胞重塑PMN以支持TNBC细胞扩增。因此，中央 该建议假设是eIF 5A 1/2在TNBC细胞中的羟腐胺赖氨酸化和细胞质定位 驱动PEAK 1依赖性TGFβ/纤连蛋白信号传导串扰和LCN 2介导的抗炎 转移前小生境的重编程以支持转移。这种方法是创新的，因为它 通过阐明目标明确的eIF 5A 1/2依赖性， 转移级联反应中早期和晚期细胞状态可塑性的翻译机制 单细胞循环免疫荧光（CycIF）平台，我们新的体内/离体无肿瘤细胞 PMN重编程试验，多功能药理学筛选方法（MAPS） 平台和一套临床前小鼠模型，忠实地概括了 人TNBC转移和进展。此外，这项研究具有重要意义，因为它 将定义eIF 5A 1/2表达失调、hypusination 和亚细胞定位驱动TNBC发病机制，并确定靶向治疗策略， 转移性TNBC。特异性目的1将确定eIF 5A 1/2的癌细胞自主机制- 介导的TNBC细胞侵袭和传播。具体目标2将识别eIF 5A 1/2依赖性 支持TNBC细胞接种和扩增的转移前小生境重编程机制。 从这些研究中获得的集体知识将阐明控制 早期和晚期TNBC转移，并建立新的治疗组合的基本原理， 克服TNBC进展并改善患者结局的方法。