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
基本信息
- 批准号:10493939
- 负责人:
- 金额:$ 40.09万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-13 至 2027-08-31
- 项目状态:未结题
- 来源:
- 关键词:Animal ModelBindingBinding SitesBreast Cancer ModelBreast cancer metastasisCellsChromatinClinicalComplement Factor BDissectionEpithelialEquilibriumFamilyGene ExpressionGenesGenetic TranscriptionGoalsImmuneImmune checkpoint inhibitorImmune systemImmuno-ChemotherapyImmunosuppressionImmunotherapyImpairmentInterferon SuppressionInterferon-betaInterferonsInterleukin-17Interleukin-6MADH3 geneMalignant NeoplasmsMediatingMesenchymalMessenger RNAMolecularNeoadjuvant TherapyPatient-Focused OutcomesPatientsPhosphorylationProductionRNA BindingRecurrenceRegulationRepressionResistance developmentSTAT1 geneSTAT2 geneSTAT3 geneSignal TransductionSpecimenStandardizationStromal CellsTestingThreonineTimeTransforming Growth Factor betaTransforming Growth FactorsTranslationsTreatment FailureTumor ImmunityViralaggressive therapyautocrinebreast cancer progressioncancer cellcancer cell differentiationcancer invasivenesscancer recurrencecancer therapycell behaviorchemotherapycytokineepigenomicsimmune system functionimprovedimproved outcomein vivomimicrynovelnovel therapeutic interventionnovel therapeuticsparacrinepreventprogramsreceptorrefractory cancerresponserestorationsensorstandard of carestemtherapy resistanttriple-negative invasive breast carcinomatumortumor microenvironment
项目摘要
PROJECT SUMMARY/ABSTRACT
Therapy failure remains an overarching clinical challenge for patients with aggressive 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 anti-tumor immunity, both of which are highly influenced by
the tumor microenvironment (TME). We find that the TME cytokines Transforming Growth Factor β (TGFβ) and
Interferon β (IFNβ) oppose one another in regulating both cancer cell differentiation and immune system function
in TNBC. TGFβ and its receptors are frequently upregulated in aggressive, therapy-resistant cancers, such as
TNBC. Mechanistically, we find that TGFβ effector SMAD3 cooperates with STAT3, an important effector of the
IL-6 family of cytokines, to induce stem-like/mesenchymal reprogramming, which enhances TNBC invasiveness,
tumor-initiating capacity, and therapeutic resistance. At the same time, TGFβ strongly suppresses IFNβ
production. Since IFNβ promotes a less aggressive cancer cell state and activates anti-tumor immunity, the
TGFβ-mediated suppression of IFNβ and its downstream effectors, STAT1 and STAT2, is an important
contributor to TNBC progression and immune system impairment. Importantly, restoration of IFNβ signaling
results in the reversal of TGFβ-mediated stem-like/mesenchymal program and re-engages anti-tumor immunity.
We hypothesize that the relative amounts of TGFβ and IFNβ cytokine activity in both cancer and immune cells
dictate TNBC aggressiveness and ultimately, patient outcomes. The purpose of our study is to define the
molecular mechanisms by which TGFβ and IFNβ antagonize one another in regulating stem-like/mesenchymal
reprogramming and anti-tumor immunity. Our Project has strong connections with Project 1, which will assess the
regulation of STAT2 by a novel threonine phosphorylation, and with Project 3 which will examine how TGFβ
synergizes with another pro-tumor cytokine, IL-17, to amplify the signals critical for repressing IFNβ production.
The unifying studies proposed in our Program will (i) identify common molecular mechanisms that promote the
development of resistance to chemo- and immune-therapies and (ii) assess novel therapeutic combinations
aimed at shifting the equilibrium of IFNβ and TGFβ/IL-17 signaling in the TME. By shifting this balance, we
propose to induce the differentiation of cancer cells and enhance anti-tumor immunity to increase the sensitivity
of hard-to-treat cancers to chemo- and immuno-therapy.
项目摘要/摘要
治疗失败仍然是侵袭性三阴乳房患者面临的首要临床挑战
癌症(TNBC)。调节TNBC转移和复发的两个重要因素是:(I)分化程度
癌细胞的状态,以及(Ii)抗肿瘤免疫的功能,这两者都受到
肿瘤微环境(TME)。我们发现TME细胞因子转化生长因子β(β)和
干扰素β对肿瘤细胞分化和免疫系统功能的调节作用相互对立
在TNBC。转化生长因子β及其受体经常在侵袭性的、耐药的癌症中上调,如
TNBC。在机制上,我们发现转化生长因子β效应器Smad3与STAT3协同作用,STAT3是Smad3的重要效应器。
IL-6家族的细胞因子,诱导干样/间充质重编程,从而增强TNBC的侵袭性,
肿瘤启动能力和治疗抵抗力。同时,转化生长因子β对干扰素β有强烈的抑制作用
制作。由于干扰素β促进较不具侵袭性的癌细胞状态并激活抗肿瘤免疫,因此
转化生长因子β介导的干扰素β及其下游效应分子STAT1和STAT2的抑制是一个重要的
导致TNBC进展和免疫系统损害的因素。重要的是,干扰素β信号的恢复
结果逆转转化生长因子β介导的干细胞/间充质细胞程序,并重新启动抗肿瘤免疫。
我们推测肿瘤细胞和免疫细胞中转化生长因子β和干扰素β细胞因子活性的相对量
决定TNBC的进攻性,并最终决定患者的预后。我们研究的目的是定义
转化生长因子β和干扰素β相互拮抗调节干细胞/间充质的分子机制
重新编程和抗肿瘤免疫。我们的项目与项目1有很强的联系,项目1将评估
通过一种新的苏氨酸磷酸化调节STAT2,以及研究转化生长因子β如何
与另一种促肿瘤细胞因子IL-17协同作用,放大抑制干扰素β产生的关键信号。
我们计划中提出的统一研究将:(I)确定共同的分子机制,促进
化疗和免疫治疗的抗药性的发展和(Ii)评估新的治疗组合
目的:改变TME中干扰素β和转化生长因子β/IL-17信号的平衡。通过改变这种平衡,我们
建议通过诱导癌细胞分化和增强抗肿瘤免疫来提高敏感性
从难以治疗的癌症到化疗和免疫治疗。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
MARK W. JACKSON其他文献
MARK W. JACKSON的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
$ 40.09万 - 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:
$ 40.09万 - 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:
$ 40.09万 - 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:
$ 40.09万 - 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:
$ 40.09万 - 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:
$ 40.09万 - 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:
$ 40.09万 - 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:
$ 40.09万 - 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:
$ 40.09万 - 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:
$ 40.09万 - 项目类别:
相似国自然基金
帽结合蛋白(cap binding protein)调控乙烯信号转导的分子机制
- 批准号:32170319
- 批准年份:2021
- 资助金额:58.00 万元
- 项目类别:面上项目
帽结合蛋白(cap binding protein)调控乙烯信号转导的分子机制
- 批准号:
- 批准年份:2021
- 资助金额:58 万元
- 项目类别:
ID1 (Inhibitor of DNA binding 1) 在口蹄疫病毒感染中作用机制的研究
- 批准号:31672538
- 批准年份:2016
- 资助金额:62.0 万元
- 项目类别:面上项目
番茄EIN3-binding F-box蛋白2超表达诱导单性结实和果实成熟异常的机制研究
- 批准号:31372080
- 批准年份:2013
- 资助金额:80.0 万元
- 项目类别:面上项目
P53 binding protein 1 调控乳腺癌进展转移及化疗敏感性的机制研究
- 批准号:81172529
- 批准年份:2011
- 资助金额:58.0 万元
- 项目类别:面上项目
DBP(Vitamin D Binding Protein)在多发性硬化中的作用和相关机制的蛋白质组学研究
- 批准号:81070952
- 批准年份:2010
- 资助金额:35.0 万元
- 项目类别:面上项目
研究EB1(End-Binding protein 1)的癌基因特性及作用机制
- 批准号:30672361
- 批准年份:2006
- 资助金额:24.0 万元
- 项目类别:面上项目
相似海外基金
Bridging the Gap: Next-Gen Tools for Accurate Prediction of Disordered Protein Binding Sites
弥合差距:准确预测无序蛋白质结合位点的下一代工具
- 批准号:
24K15172 - 财政年份:2024
- 资助金额:
$ 40.09万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Design of protein crystal templates with multiple binding sites for tracking metal complex reactions.
设计具有多个结合位点的蛋白质晶体模板,用于跟踪金属络合物反应。
- 批准号:
23K04928 - 财政年份:2023
- 资助金额:
$ 40.09万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Dynamic changes in PIP2 binding sites and their impact on axonal targeting and function of epilepsy-associated KCNQ/Kv7 channels
PIP2 结合位点的动态变化及其对癫痫相关 KCNQ/Kv7 通道的轴突靶向和功能的影响
- 批准号:
10744934 - 财政年份:2023
- 资助金额:
$ 40.09万 - 项目类别:
Computational methods to identify small molecule RNA binding sites
识别小分子 RNA 结合位点的计算方法
- 批准号:
573688-2022 - 财政年份:2022
- 资助金额:
$ 40.09万 - 项目类别:
University Undergraduate Student Research Awards
Identification of potential drug binding sites within allosteric networks in cyclic nucleotide modulated channels
环核苷酸调节通道变构网络内潜在药物结合位点的鉴定
- 批准号:
10704557 - 财政年份:2022
- 资助金额:
$ 40.09万 - 项目类别:
Identification of potential drug binding sites within allosteric networks in cyclic nucleotide modulated channels
环核苷酸调节通道变构网络内潜在药物结合位点的鉴定
- 批准号:
10537846 - 财政年份:2022
- 资助金额:
$ 40.09万 - 项目类别:
Identifying new types of inhibitors in quinone binding sites in photosynthetic enzymes
鉴定光合酶醌结合位点的新型抑制剂
- 批准号:
2753921 - 财政年份:2022
- 资助金额:
$ 40.09万 - 项目类别:
Studentship
Development of broad nanovaccines targeting diverse coronavirus receptor-binding sites
开发针对不同冠状病毒受体结合位点的广泛纳米疫苗
- 批准号:
10328140 - 财政年份:2022
- 资助金额:
$ 40.09万 - 项目类别:
Exploiting Water Network Perturbations in Protein Binding Sites
利用蛋白质结合位点的水网络扰动
- 批准号:
10621368 - 财政年份:2021
- 资助金额:
$ 40.09万 - 项目类别:
SBIR Phase I: Nonlinear optical method for identifying protein-ligand binding sites
SBIR 第一阶段:识别蛋白质-配体结合位点的非线性光学方法
- 批准号:
2111821 - 财政年份:2021
- 资助金额:
$ 40.09万 - 项目类别:
Standard Grant