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: 10546451
• 负责人: Jonathan Kelber
• 金额: $ 36.25万
• 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/10546451
• 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; Cytoplasm; Data; Eukaryotic Initiation Factors; Fibronectins; Flow Cytometry; Funding; Goals; Heterogeneity; Human; Immunofluorescence Immunologic; Inflammatory; Integrins; Intervention; Invaded; 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; Up-Regulation; Work; aggressive breast cancer; breast cancer progression; cancer cell; cancer subtypes; cancer type; eIF-5A; genetic manipulation; improved; in vivo; innovation; mortality; mouse model; neoplastic cell; novel; novel therapeutic intervention; novel therapeutics; nucleocytoplasmic transport; pharmacologic; pre-clinical; programs; 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.

项目总结 转移是实体瘤患者死亡的首要原因。因为在临床上没有- 批准的靶向治疗三阴性乳腺癌(TNBC)，转移性TNBC前期 发出可怕的临床情况，迫切需要干预策略。长期目标 这项建议的目的是阐明肿瘤细胞自主和非自主的新机制 推动TNBC进展和转移。这项提案的总体目标是定义分子-- 真核生物翻译后下化和核质转运的LAR/细胞基础 启动因子5A(eIF5A1/2)调控伪足富集型非典型激酶1(PEAK1)依赖 侵袭/扩散和Lipocalin 2(Lcn2)介导的转移前生态位重编程 (PMN)。为此，有证据表明eIF5A1/2激活/激活途径 与TNBC预后不良有关，是转化生长因子β/PEAK1诱导的转移和Lcn2所必需的 在TNBC细胞中表达。此外，eIF5A1/2-Lcn2轴被确定为一种新的机制 原代肿瘤细胞通过它重塑PMN以支持TNBC细胞的扩张。因此，中央 这一假设是eIF5A1/2在TNBC细胞中的激活和胞浆定位 驱动依赖PEAK1的转化生长因子β/纤维连接蛋白信号串扰和LCN2介导的抗炎 对转移前的生态位重新编程以支持转移。这种方法是创新的，因为它 通过阐明有针对性的eIF5A1/2依赖，代表了对现状的实质性偏离 细胞状态可塑性在转移级联早期和晚期的翻译机制 单细胞循环免疫荧光(CycIF)平台--我们新的体内/体外无肿瘤细胞 PMN重编程试验--多功能药理筛选方法(MAP) 平台和一套临床前小鼠模型，忠实地概括了 人TNBC的转移和进展。此外，拟议的研究具有重要意义，因为它 将定义eIF5A1/2表达失调、下激化的时空机制 和亚细胞定位驱动TNBC的发病机制并确定有针对性的治疗策略 转移性TNBC。特异性靶点1将确定eIF5A1/2的癌细胞自主机制- 介导TNBC细胞的侵袭和扩散。特定目标2将确定eIF5A1/2依赖 支持TNBC细胞播种和扩增的转移前生态位重新编程机制。 从这些研究中获得的集体知识将阐明有针对性的机制 TNBC转移的早期和晚期，并为新的治疗组合奠定了理论基础。 克服TNBC进展和改善患者预后的治疗措施。