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:10211081
- 负责人:
- 金额:$ 41.28万
- 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.
抽象的
癌细胞的转移扩散和复发与治疗失败密切相关,这仍然是一个问题
转移性三阴性乳腺癌(TNBC)患者面临的重要临床挑战。两个重要的
调节 TNBC 转移和复发的因素是:(i) 癌细胞的分化状态,以及
(ii) 免疫系统的功能
肿瘤微环境(TME)。癌细胞和
免疫细胞受到细胞因子制瘤素 M (OSM) 和干扰素-β (IFNB) 的高度影响。我们发现
OSM 和 IFNB 在调节癌细胞分化和免疫方面的作用是相反的
TME 内的系统功能。 OSM 及其受体 (OSMR) 在攻击性、
转移性和治疗耐药的复发性癌症,例如 TNBC。从机制上讲,OSM/OSMR 引发了强大的
STAT3 的激活,与 SMAD3 形成转录复合物,并诱导干细胞样/间充质细胞
增强 TNBC 侵袭性和对化疗和免疫治疗的抵抗力的计划。此外,
STAT3 和 SMAD3 在共同依赖的基因启动子上的合作产生促炎、肿瘤-
通过抑制免疫激活 IFNB 的产生并诱导免疫抑制来促进 TME
细胞因子。恢复 IFNB 信号传导可预防和逆转干细胞样/间质编程
OSMR 和 STAT3/SMAD3。因此,STAT3 和 SMAD3 之间的合作使 IFNB :STAT1/2 失活
信号轴代表转移进展和肿瘤复发的关键步骤。基于这些和其他
令人信服的发现,我们将检验 OSM:STAT3/SMAD3 和
TNBC 细胞和免疫细胞中的 IFNB :STAT1/2 信号传导决定转移复发并最终导致患者
结果。我们将在两个具体目标中测试这一假设:目标 1 将确定 IFNB 如何抑制 OSMR-
介导 STAT3/SMAD3 共依赖性基因表达;目标 2 将定义 OSMR/ERK 信号传导如何激活
STAT3/SMAD3 驱动干细胞样/间质重编程和抑制 IFNB/ISG。一起,
我们的研究结果将有助于更好地理解 OSM 的分子机制
和 IFNB 相互拮抗并测试新的治疗方法以将平衡转向主动
TNBC 和免疫细胞中 IFNB :STAT1/2 并远离 OSMR:STAT3/SMAD3,目的是改善
转移性 TNBC 患者的结局。
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:
$ 41.28万 - 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:
$ 41.28万 - 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:
10364703 - 财政年份:2021
- 资助金额:
$ 41.28万 - 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
- 资助金额:
$ 41.28万 - 项目类别:
Defining the role of FAM83B in lung cancer using a new mouse model
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10201807 - 财政年份:2021
- 资助金额:
$ 41.28万 - 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:
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10469505 - 财政年份:2018
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$ 41.28万 - 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:
10678931 - 财政年份:2018
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$ 41.28万 - 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:
9752503 - 财政年份:2018
- 资助金额:
$ 41.28万 - 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:
$ 41.28万 - 项目类别:
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