Elucidation of mutant p53-medidated mechanisms in promoting metastatic esophageal cancer
阐明突变型 p53 介导的促进转移性食管癌的机制
基本信息
- 批准号:10689716
- 负责人:
- 金额:$ 4.68万
- 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:2022-09-01 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalATAC-seqAdvisory CommitteesAffectAutocrine CommunicationAwardBindingBromodomainCSF1R geneCancer EtiologyCell LineCellsChromatinClinicalCommunicationDNA BindingDNA Binding DomainDataDevelopment PlansDiagnosisDiseaseEpigenetic ProcessEsophageal Squamous Cell CarcinomaEsophageal carcinomaEventFacultyFoundationsFutureGeneticGenetic TranscriptionGenomicsGoalsGrantHomologous GeneHumanIn VitroInstitutionInvadedM cellMacrophageMacrophage Colony-Stimulating FactorMalignant Epithelial CellMalignant NeoplasmsMalignant neoplasm of esophagusManuscriptsMediatingMediatorMedical centerMentorshipMetastatic Neoplasm to the LungMissense MutationModelingMolecular ConformationMusMutateMutationNeoplasm MetastasisOncogenicOrganoidsOutcomePathway interactionsPatientsPositioning AttributePostdoctoral FellowPre-Clinical ModelPrimary NeoplasmPrognosisProliferatingPropertyReaderRecurrenceResourcesRoleScientistSignal PathwaySignal TransductionSquamous cell carcinomaSurvival RateTP53 geneTestingTherapeuticThinkingTrainingTumor Cell InvasionTumor PromotionTumor Suppressor ProteinsTumor-associated macrophagesUniversitiesUp-RegulationWorkWritinganticancer researchbase editingcancer typecareercareer developmentcollaborative environmenteffective therapygain of functionimprovedin vivoin vivo Modelmetastatic esophagealmigrationmortalitymouse modelmutantneoplastic cellnew therapeutic targetnovel therapeutic interventionpharmacologicprogramsreceptorskillssmall hairpin RNAsmall moleculetenure tracktranscriptome sequencingtranscriptomicstumortumor growthtumorigenesistumorigenic
项目摘要
PROJECT SUMMARY
Esophageal Squamous Cell Carcinoma (ESCC), the predominant subtype of esophageal cancer worldwide is
one of the most known lethal cancers. The prognosis of metastatic ESCC is dismal with a 5-year relative survival
rate of only 5%. Mutations in TP53 (mouse homolog Trp53), which are detected in approximately 70% of ESCC
patients, contribute to tumor metastasis and poor prognosis. To understand the mechanisms of Trp53R172H-
mediated metastasis, which is one of the “hotspot” mutations in ESCC, we utilized mouse models and performed
RNA-Seq on metastatic ESCC cells generated from this model, from which I identified Colony stimulating factor-
1 (Csf-1) to be significantly upregulated. While it is canonically involved in polarization of tumor-associated
macrophages through binding to its receptor CSF-1R, my data demonstrate the existence of autocrine signaling
that is potentially co-regulated by epigenetic reader Bromodomain-Containing Domain 4 (BRD4). The
overarching hypothesis of this study is that CSF-1/CSF-1R autocrine signaling is one of the major mechanisms
by which missense TP53 mutations can promote invasion and lung metastasis in ESCC. I will test this hypothesis
through the following interrelated Specific Aims: (1) Elucidate the role of Trp53R172H-mediated CSF-1/CSF-1R
signaling pathway in promoting invasion and lung metastasis in ESCC, (2) Investigate BRD4 as a candidate co-
regulator of Trp53R172H that contributes to CSF-1 upregulation and assess the anti-tumorigenic efficacy of
inhibiting BRD4, and (3) Delineate the tumorigenic, as well as epigenetic/transcriptomic states mediated by
missense p53 mutations recurrent in ESCC patients and impact upon CSF-1/CSF-1R signaling. To accomplish
Aim 1, I will assess the role of CSF-1/CSF-1R signaling in proliferation, migration, primary tumor and 3D organoid
formation, invasion and lung metastasis, as well as its downstream effectors through utilizing in vitro and
complementary in vivo approaches. I will accomplish Aim 2 by studying the direct interaction of p53-R172H and
BRD4, and also their shared DNA binding motifs through CUT&RUN-Seq. Additionally, I will genetically delete
and pharmacologically inhibit BRD4 to evaluate their effects on tumorigenesis and lung metastasis. To
accomplish Aim 3, I will introduce p53 mutations through base editing and evaluate their distinct roles in pro-
oncogenic activities. I will also investigate how these mutations affect the transcriptional expression of factors in
CSF-1/CSF-1R signaling pathway during metastasis, and also conduct single-cell ATAC-Seq on mouse primary
and metastatic tumors to evaluate their chromatin accessibility. This study will elucidate the tumor cell intrinsic
mechanisms underlying ESCC metastasis, which will ultimately open new avenues in developing therapeutic
strategies for metastatic ESCC patients that can be extended to other SCCs. I will develop skills in analytical
thinking, technical approaches, scientific communication, grant and manuscript writing, and mentorship with the
support and resources available through my sponsors, advisory committee and graduate program, which will be
critical to accomplish my long-standing career goal to become a tenure-track faculty to conduct cancer research.
项目摘要
食管鳞状细胞癌(ESCC)是世界范围内食管癌的主要亚型,
最著名的致命癌症之一转移性食管鳞癌的预后很差,相对生存期只有5年
率仅为5%。TP 53(小鼠同源物Trp 53)突变,在约70%的ESCC中检测到
患者,有助于肿瘤转移和不良预后。为了了解Trp 53 R172 H-的作用机制,
介导的转移,这是ESCC中的“热点”突变之一,我们利用小鼠模型,
从该模型产生的转移性ESCC细胞上的RNA-Seq,从中我鉴定出集落刺激因子-
1(Csf-1)显著上调。虽然它通常参与肿瘤相关的极化,
巨噬细胞通过结合其受体CSF-1 R,我的数据表明存在自分泌信号
其潜在地由表观遗传阅读器含溴结构域4(BRD 4)共调节。的
本研究的总体假设是CSF-1/CSF-1 R自分泌信号传导是主要机制之一,
TP 53错义突变可促进食管鳞癌的侵袭和肺转移。我将检验这个假设
(1)阐明Trp 53 R172 H介导的CSF-1/CSF-1 R在细胞内的作用
(2)研究BRD 4在ESCC侵袭和肺转移中的作用,
Trp 53 R172 H的调节子,其有助于CSF-1上调并评估Trp 53 R172 H的抗肿瘤功效。
抑制BRD 4,和(3)描述肿瘤发生,以及表观遗传/转录组学状态介导的
错义p53突变在ESCC患者中复发并影响CSF-1/CSF-1 R信号传导。完成
目的1:探讨CSF-1/CSF-1 R信号通路在肿瘤细胞增殖、迁移、原发性肿瘤和三维类器官中的作用
形成、侵袭和肺转移,以及其下游效应物,
补充体内方法。我将通过研究p53-R172 H和p53-R172 H之间的直接相互作用来实现目标2。
BRD 4,以及它们通过CUT&RUN-Seq共享的DNA结合基序。另外,我会从基因上删除
和BRD 4抑制剂来评价它们对肿瘤发生和肺转移的影响。到
为了实现目标3,我将通过碱基编辑引入p53突变,并评估它们在促凋亡中的不同作用。
致癌活性。我还将研究这些突变如何影响转录因子的表达,
转移过程中CSF-1/CSF-1 R信号通路,并在小鼠原发性肝癌细胞上进行单细胞ATAC-Seq。
和转移性肿瘤来评估它们的染色质可及性。这项研究将阐明肿瘤细胞的内在
ESCC转移的潜在机制,这将最终开辟新的途径,在发展治疗
转移性ESCC患者的策略,可以扩展到其他SCC。我将培养分析能力
思维,技术方法,科学交流,赠款和手稿写作,以及与
通过我的赞助商、咨询委员会和研究生项目获得的支持和资源,
这对实现我长期以来的职业目标,成为一名从事癌症研究的终身教职人员至关重要。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Gizem Efe', 18)}}的其他基金
Elucidation of mutant p53-medidated mechanisms in promoting metastatic esophageal cancer
阐明突变型 p53 介导的促进转移性食管癌的机制
- 批准号:
10537915 - 财政年份:2022
- 资助金额:
$ 4.68万 - 项目类别:
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