Targeting Oncostatin M-Receptor to Suppress Metastasis and Therapy Failure
靶向制瘤素 M 受体抑制转移和治疗失败
基本信息
- 批准号:10364703
- 负责人:
- 金额:$ 40.46万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-03-04 至 2026-02-28
- 项目状态:未结题
- 来源:
- 关键词:BindingBreast Cancer CellBreast cancer metastasisCBL geneCell Culture TechniquesCellsClinicalCombined Modality TherapyComplexDiseaseDrug ToleranceEquilibriumGene ExpressionGenerationsGenesGenetic TranscriptionGoalsHumanImmuneImmune checkpoint inhibitorImmune systemImmuno-ChemotherapyImmunosuppressive AgentsInflammatoryInterferon-betaLeadLinkMADH3 geneMaintenanceMediatingMesenchymalMolecularNeoplasm MetastasisPatient-Focused OutcomesPatientsPhosphorylationPlant RootsPopulationProductionRecurrenceRecurrent Malignant NeoplasmRelapseRepressionResistanceSTAT1 geneSTAT2 geneSTAT3 geneSeedsSignal TransductionTestingTreatment FailureTumor ImmunityViralbasecancer cellcancer cell differentiationcancer invasivenesscancer recurrencechemotherapycytokineimmune system functionimprovedimproved outcomemimicrymouse modelnanoparticlenovelnovel therapeutic interventiononcostatin Mpreventprogramspromoterreceptorsensorstandard of carestemstem-like celltherapy resistanttranscription factortriple-negative invasive breast carcinomatumortumor microenvironment
项目摘要
ABSTRACT
The metastatic spread of cancer cells and recurrence are intimately linked to therapy failure, which remains an
important clinical challenge for patients with metastatic Triple Negative Breast Cancer (TNBC). Two important
factors that regulate TNBC metastasis and recurrence are: (i) the differentiation status of the cancer cells, and
(ii) the functionality of the immune system within the
tumor microenvironment (TME). Both the cancer cells and
the immune cells are highly influenced by the cytokines Oncostatin M (OSM) and Interferon-beta (IFNB). We find
that the actions of OSM and IFNB oppose one another in regulating both cancer cell differentiation and immune
system function within the TME. OSM and its receptor (OSMR) are frequently upregulated in aggressive,
metastatic and therapy-resistant recurrent cancers, such as TNBC. Mechanistically, OSM/OSMR elicits robust
activation of STAT3, which forms a transcriptional complex with SMAD3, and induces stem-like/mesenchymal
programs that enhance TNBC aggressiveness and resistance to chemo- and immuno-therapy. Moreover, the
cooperation of STAT3 and SMAD3 on co-dependent gene promoters produces a pro-inflammatory, tumor-
promoting TME by suppressing the production of immune-activating IFNB and inducing immune-inhibitory
cytokines. Restoring IFNB signaling prevents and reverses stem-like/mesenchymal programming stimulated by
OSMR and STAT3/SMAD3. Thus, the cooperation between STAT3 and SMAD3 to inactivate IFNB :STAT1/2
signaling axis represents a key step in metastatic progression and tumor recurrence. Based on these and other
compelling findings, we will test the hypothesis that the relative balance between OSM:STAT3/SMAD3 and
IFNB :STAT1/2 signaling in both TNBC cells and immune cells dictates metastatic relapse and ultimately, patient
outcomes. We’ll test this hypothesis in two Specific Aims: Aim 1 will determine how IFNB suppresses OSMR-
mediated STAT3/SMAD3 co-dependent gene expression; Aim 2 will define how OSMR/ERK signaling activates
STAT3/SMAD3 to drive stem-like/mesenchymal reprogramming and the suppression of IFNB/ISGs. Together,
the results from our studies will provide a greater understanding of the molecular mechanisms by which OSM
and IFNB antagonize one another and test novel therapeutic approaches to shift the balance towards active
IFNB :STAT1/2 and away from OSMR:STAT3/SMAD3 in both TNBC and immune cells, with the goal of improving
outcomes for patients with metastatic TNBC.
摘要
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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MARK W. JACKSON其他文献
MARK W. JACKSON的其他文献
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{{ truncateString('MARK W. JACKSON', 18)}}的其他基金
Shifting the balance between IFN-I and TGF-beta to improve cancer therapy
改变 IFN-I 和 TGF-β 之间的平衡以改善癌症治疗
- 批准号:
10704231 - 财政年份:2022
- 资助金额:
$ 40.46万 - 项目类别:
Shifting the balance between IFN-I and TGF-beta to improve cancer therapy
改变 IFN-I 和 TGF-β 之间的平衡以改善癌症治疗
- 批准号:
10493939 - 财政年份:2022
- 资助金额:
$ 40.46万 - 项目类别:
Targeting Oncostatin M-Receptor to Suppress Metastasis and Therapy Failure
靶向制瘤素 M 受体抑制转移和治疗失败
- 批准号:
10576854 - 财政年份:2021
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$ 40.46万 - 项目类别:
Defining the role of FAM83B in lung cancer using a new mouse model
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$ 40.46万 - 项目类别:
Defining the role of FAM83B in lung cancer using a new mouse model
使用新的小鼠模型定义 FAM83B 在肺癌中的作用
- 批准号:
10373095 - 财政年份:2021
- 资助金额:
$ 40.46万 - 项目类别:
Targeting Oncostatin M-Receptor to Suppress Metastasis and Therapy Failure
靶向制瘤素 M 受体抑制转移和治疗失败
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- 资助金额:
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Cancer-focused Summer Undergraduate Research (CanSUR) Program
以癌症为重点的暑期本科生研究 (CanSUR) 计划
- 批准号:
10678931 - 财政年份:2018
- 资助金额:
$ 40.46万 - 项目类别:
Cancer-focused Summer Undergraduate Research (CanSUR) Program
以癌症为重点的暑期本科生研究 (CanSUR) 计划
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- 资助金额:
$ 40.46万 - 项目类别:
Cancer-focused Summer Undergraduate Research (CanSUR) Program
以癌症为重点的暑期本科生研究 (CanSUR) 计划
- 批准号:
10248314 - 财政年份:2018
- 资助金额:
$ 40.46万 - 项目类别:
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