Regulation of the tumor microenvironment by DNA damage repair proteins
DNA损伤修复蛋白调节肿瘤微环境
基本信息
- 批准号:10737565
- 负责人:
- 金额:$ 31.31万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-14 至 2024-01-15
- 项目状态:已结题
- 来源:
- 关键词:AffectAntibodiesBreast Cancer CellCell CommunicationCell Culture TechniquesCellsClinicalCytosolDNADNA RepairDNA Sequence AlterationDataDependenceDiagnosisDimerizationERBB2 geneErbB4 geneEstrogen receptor positiveExperimental ModelsFDA approvedFamily memberGenome StabilityGoalsGrowthHeterodimerizationImpairmentIn SituIn VitroInflammatoryLigand BindingLigand Binding DomainLigandsLinkMLH1 geneMalignant NeoplasmsMammary NeoplasmsMediatingMetastatic breast cancerMismatch RepairMutagenesisMutateMutationNeuregulin 1Pathway interactionsPatientsPatternPhenotypePredictive ValuePredispositionProteinsPublishingRNA InterferenceReceptor Protein-Tyrosine KinasesRegulationResearchResistanceRoleSeminalSignal TransductionStimulator of Interferon GenesTestingTherapeuticTumor Suppressor ProteinsWomanWorkbehavior influencebetacellulincancer cellcancer diagnosiscarcinogenesiscytokinedigitalheparin-binding EGF-like growth factorhormone therapyin vivoinhibitorinsightinterestmalignant breast neoplasmneoplastic cellnovelnovel therapeutic interventionoverexpressionpredicting responseprognostic valueresistance mechanismtherapy resistanttreatment responsetumortumor behaviortumor growthtumor microenvironment
项目摘要
PROJECT SUMMARY
Background ER+ breast cancer accounts for 2/3 of invasive breast cancer cases diagnosed in the world today. In
patients, ~12% of ER+ tumors have complete loss of MLH1, a tumor suppressor and mismatch repair protein.
We previously showed that MLH1 loss in ER+ breast cancer cells activates HER2 to induce resistance to standard
endocrine therapy. However, the underlying mechanism remains unknown. Preliminary data support a role for
MLH1 loss in altering secretion of HER ligands to mediate HER2 activation. This is of particular interest because
an additional 14% of ER+ patient tumors have heterogeneous loss of MLH1. Although the functional consequence
of heterogeneous MLH1 loss is as yet unknown, a role for MLH1 loss in altering the cancer secretome suggests
a potentially significant impact on bulk tumor phenotypes.
Hypothesis Based on our published work and preliminary data, the proposed study will test the hypothesis that
MLH1 loss in ER+ breast cancer induces secretion of HER ligands, by co-opting cGAS-STING signaling, to
promote HER2-dependent growth of both MLH1– and MLH1+ cells in heterogeneously MLH1– tumors.
Specific Aims Aim 1 will test whether the secretion of HER ligands induced by MLH1 loss mediates HER2
activation to promote endocrine therapy resistance. Here, we will use both in vitro and in vivo approaches to
determine whether the ligands secreted by MLH1- ER+ breast cancer cells promote HER2 heterodimerization
and consequent activation, and thereby endocrine therapy resistant growth. Aim 2 will investigate the mechanism
linking MLH1 loss to HER ligand secretion. Specifically, we will test whether inefficient DNA damage repair in
the absence of MLH1 triggers the cGAS-STING secretory pathway. We will also determine how cGAS-STING
activation promotes HER ligand secretion. Aim 3 will examine the therapeutic impact of heterogeneous MLH1
loss. Using in vitro and in vivo experimental models established in my lab, we will test whether HER2 activation
in both MLH1+ and MLH1- cells in tumors with heterogeneous MLH1 loss renders these tumors globally
susceptible to HER2 inhibitors. We will also use digital spatial profiling to assess the contribution of the secretome
to signaling patterns and therapeutic response in heterogeneously MLH1- tumors.
Impact The results of this study will present new therapeutic strategies to help >25,000 women diagnosed each
year with ER+ breast cancer characterized by heterogeneous MLH1 loss. Our work will also provide novel insight
into how MLH1 loss modulates the cGAS-STING pathway to promote a pro-growth tumor secretome. Overall,
results from this study will shed new insight into the how MLH1 loss promotes cancer phenotypes.
项目摘要
背景ER+乳腺癌占当今世界诊断的浸润性乳腺癌病例的2/3。在
大约12%的ER+肿瘤完全丧失MLH 1,一种肿瘤抑制因子和错配修复蛋白。
我们先前表明ER+乳腺癌细胞中MLH 1的缺失激活HER 2,诱导对标准抗肿瘤药物的耐药性。
内分泌治疗然而,其潜在机制仍不清楚。初步数据表明,
改变HER配体分泌以介导HER 2活化的MLH 1损失。这一点特别重要,因为
另外14%的ER+患者肿瘤具有MLH 1的异质性缺失。虽然功能性后果
异质性MLH 1丢失的原因尚不清楚,MLH 1丢失在改变癌症分泌组中的作用表明,
对大部分肿瘤表型具有潜在的显著影响。
假设基于我们已发表的工作和初步数据,拟议的研究将测试假设,
ER+乳腺癌中的MLH 1缺失通过选择cGAS-STING信号传导诱导HER配体分泌,
促进异质性MLH 1-肿瘤中MLH 1-和MLH 1+细胞的HER 2依赖性生长。
特定目的目的1将测试由MLH 1缺失诱导的HER配体分泌是否介导HER 2
激活,以促进内分泌治疗抗性。在这里,我们将使用体外和体内方法,
确定MLH 1- ER+乳腺癌细胞分泌的配体是否促进HER 2异源二聚化
和随后的激活,从而抵抗内分泌治疗的生长。目标2将研究其机制
将MLH 1丢失与HER配体分泌联系起来。具体地说,我们将测试是否低效的DNA损伤修复,
MLH 1的缺失触发cGAS-STING分泌途径。我们还将确定cGAS-STING
激活促进HER配体分泌。目的3将检查异质性MLH 1的治疗效果。
损失我们将利用本实验室建立的体外和体内实验模型,
在具有异质性MLH 1缺失的肿瘤中的MLH 1+和MLH 1-细胞中,
对HER 2抑制剂敏感。我们还将使用数字空间分析来评估分泌组的贡献
信号模式和治疗反应在异质MLH 1肿瘤。
这项研究的结果将提出新的治疗策略,以帮助> 25,000名妇女诊断,
以异质性MLH 1丢失为特征的ER+乳腺癌患者。我们的工作还将提供新的见解
MLH 1缺失如何调节cGAS-STING通路以促进促生长肿瘤分泌组。总的来说,
这项研究的结果将为MLH 1缺失如何促进癌症表型提供新的见解。
项目成果
期刊论文数量(0)
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Svasti Haricharan其他文献
Svasti Haricharan的其他文献
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{{ truncateString('Svasti Haricharan', 18)}}的其他基金
Regulation of the tumor microenvironment by DNA damage repair proteins
DNA损伤修复蛋白调节肿瘤微环境
- 批准号:
10998271 - 财政年份:2023
- 资助金额:
$ 31.31万 - 项目类别:
A pan-cancer role for MutL loss in inducing treatment resistance
MutL 缺失在诱导治疗抵抗中的泛癌作用
- 批准号:
9583001 - 财政年份:2018
- 资助金额:
$ 31.31万 - 项目类别:
A pan-cancer role for MutL loss in inducing treatment resistance
MutL 缺失在诱导治疗抵抗中的泛癌作用
- 批准号:
9765215 - 财政年份:2018
- 资助金额:
$ 31.31万 - 项目类别:
A pan-cancer role for MutL loss in inducing treatment resistance
MutL 缺失在诱导治疗抵抗中的泛癌作用
- 批准号:
10001982 - 财政年份:2018
- 资助金额:
$ 31.31万 - 项目类别:
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