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
基本信息
- 批准号:10546451
- 负责人:
- 金额:$ 36.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:3-DimensionalAdhesionsAffectAnti-Inflammatory AgentsBiochemistryBiological AssayBreast Cancer CellBreast Cancer ModelBreast Cancer PatientBreast cancer metastasisCancer BiologyCancer PrognosisCell Cycle KineticsCellsCellular biologyChemotherapy-Oncologic ProcedureClinicalComplexCytoplasmDataEukaryotic Initiation FactorsFibronectinsFlow CytometryFundingGoalsHeterogeneityHumanImmunofluorescence ImmunologicInflammatoryIntegrinsInterventionInvadedKnowledgeLCN2 geneLaboratoriesMediatingMethodsModelingMolecularNeoplasm MetastasisOncologyOutcomePathogenesisPathway interactionsPatient-Focused OutcomesPatientsPeriodicityPharmacologyPhosphotransferasesPre-Clinical ModelPrimary NeoplasmProteinsPublishingReportingResearchSignal TransductionSiteSolid NeoplasmTestingTissuesTransforming Growth Factor betaUp-RegulationWorkaggressive breast cancerbreast cancer progressioncancer cellcancer subtypescancer typeeIF-5Agenetic manipulationimprovedin vivoinnovationmortalitymouse modelneoplastic cellnovelnovel therapeutic interventionnovel therapeuticsnucleocytoplasmic transportpharmacologicpre-clinicalprogramspublic health relevanceresponsescreeningspatiotemporaltargeted treatmenttreatment strategytriple-negative invasive breast carcinomatumortumor progressiontumorigenesis
项目摘要
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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Jonathan Kelber其他文献
Jonathan Kelber的其他文献
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{{ truncateString('Jonathan Kelber', 18)}}的其他基金
California State University - Interdisciplinary Cancer Meeting (CSU-ICM)
加州州立大学 - 跨学科癌症会议 (CSU-ICM)
- 批准号:
10539868 - 财政年份:2022
- 资助金额:
$ 36.25万 - 项目类别:
Non-Transcriptional Mechanisms of PEAK1 Action During TGFbeta-Induced EMT
TGFbeta 诱导的 EMT 过程中 PEAK1 作用的非转录机制
- 批准号:
9208078 - 财政年份:2017
- 资助金额:
$ 36.25万 - 项目类别:
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:
10724839 - 财政年份:2017
- 资助金额:
$ 36.25万 - 项目类别:
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 - 财政年份:2017
- 资助金额:
$ 36.25万 - 项目类别:
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:
10088942 - 财政年份:2017
- 资助金额:
$ 36.25万 - 项目类别:
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 - 财政年份:2017
- 资助金额:
$ 36.25万 - 项目类别:
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:
10374539 - 财政年份:2017
- 资助金额:
$ 36.25万 - 项目类别:
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:
10360453 - 财政年份:2017
- 资助金额:
$ 36.25万 - 项目类别:
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