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

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)
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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
  • 资助金额:
    $ 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:
    10201807
  • 财政年份:
    2021
  • 资助金额:
    $ 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
  • 批准号:
    10211081
  • 财政年份:
    2021
  • 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:
    10469505
  • 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
  • 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
  • 批准号:
    9752503
  • 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
  • 批准号:
    10248314
  • 财政年份:
    2018
  • 资助金额:
    $ 40.46万
  • 项目类别:

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