PDCD10 as a novel driver for head and neck squamous cell carcinoma development
PDCD10作为头颈鳞状细胞癌发展的新型驱动因素
基本信息
- 批准号:10648001
- 负责人:
- 金额:$ 24.6万
- 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:2023-08-01 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:Alcohol consumptionAnimalsApoptosisAutomobile DrivingBioinformaticsBiological MarkersBiologyCarcinogensCell MaintenanceCell ProliferationCell physiologyCessation of lifeChemoresistanceCoupledDataData SetDetectionDevelopmentDiagnosisDiseaseDysplasiaEndowmentEpitheliumEventEvolutionExposure toGenesGenomicsHead and Neck Squamous Cell CarcinomaHead and neck structureHistologicHistopathologic GradeHumanHuman CharacteristicsHuman PapillomavirusHuman papilloma virus infectionHyperkeratosisIncidenceKnock-outKnowledgeLesionLinkLoxP-flanked alleleMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of lungMediatingMesenchymalModelingMolecularMorbidity - disease rateMorphologyMucous MembraneMusOncogenesOncogenicOralOral StageOrganoidsPathway interactionsPatientsPatternPersonsPhenotypePhysiologyPlayPre-Clinical ModelPrevalencePrognosisPrognostic MarkerProteinsProtocols documentationQuality ControlRegulationReportingRiskRisk AssessmentRoleSamplingSignal PathwaySignal TransductionSiteSmall IntestinesSolidSpecimenSquamous EpitheliumTamoxifenTherapeuticTherapeutic InterventionTongueTumor PromotionUp-RegulationWild Type Mouseanti-canceranti-tumor immune responsebeta catenincancer stem cellcarcinogenesiscell behaviorcohortdesigndrinking watereffective therapyimprovedin vivoinhibitorinsightinterestlongitudinal analysislongitudinal datasetmalignant breast neoplasmmalignant mouth neoplasmmalignant oropharynx neoplasmmortalitymouse modelmouth squamous cell carcinomaneoplasticneoplastic cellnew therapeutic targetnovelnovel strategiesoral tumorigenesisorganizational structureoverexpressionpatient prognosispre-clinicalself organizationself-renewalstem cell functionstem cell populationstem cell self renewalstem cell survivalstem cell therapystem cellsstemnesstargeted treatmenttherapeutic targettobacco productstooltranscriptome sequencingtranscriptomicstumortumor progressiontumorigenesis
项目摘要
Summary
Oral cavity squamous cell carcinoma (OCSCC), the most common subtype of head and neck squamous cell
carcinoma (HNSCC), is a devastating disease, causing substantial morbidity and mortality. Consumption of
alcohol and tobacco products increases the risk of OCSCC. Prevalence of human papilloma virus (HPV) infection
outside of oropharyngeal cancer is low, and its significance remains debatable. Only a handful of targeted
therapies are available for patients with HPV-negative HNSCC (which include many oral cavity cancers), and
the 5-year overall survival remains ~50%. While strategies are being designed to improve risk assessment,
detection, and therapeutic intervention, these approaches are limited by our incomplete understanding of
HNSCC biology, particularly in its early development. Thus, it is crucial to identify novel targets of therapeutic
interest.
PDCD10 is a multifaceted protein shown to be overexpressed in several solid malignancies. It was reported that
PCDC10 regulates numerous oncogenic pathways and may contribute to tumorigenesis and chemoresistance
by promoting cell proliferation, anti-apoptosis, epithelial-mesenchymal transition, and inhibiting anti-tumor
immune responses. Recently it was suggested that PDCD10 is involved in regulating cancer stem cells (CSCs)
maintenance in breast and lung cancers. In line with these observations, our studies suggest that PDCD10 plays
an important role in promoting Wnt/β-catenin mediated stem cell maintenance in small intestines. Notably,
preliminary data outlined below provide strong evidence for an equivalent role of PDCD10 in HNSCC, and
suggest that upregulation of its expression is an important event in neoplastic progression, posing PDCD10 as
a valuable prognostic biomarker and a potential therapeutic target.
While PDCD10 is being actively studied in several preclinical settings, there is limited data on its role in head
and neck tumorigenesis. In this proposal we will use in vivo and organoid based preclinical models, coupled with
comprehensive bioinformatics analysis of longitudinally collected primary human specimens, to evaluate the role
of PDCD10 in HNSCC evolution and driving aggressive tumor cells behavior. Our project pursues three
independent Aims. Specifically: Aim 1 will use mice model with inducible Pdcd10 knockout in tongue epithelia
to evaluate the ability of PDCD10 depletion to inhibit oral cancerogenesis in vivo; Aim 2 will use human OCSCC
organoid models to assess the ability of PDCD10 to promote CSCs survival and self-renewal; while Aim 3 will
use a unique already existing RNA-Seq dataset of longitudinally collected oral dysplastic lesions and OCSCC
samples to delineate key PDCD10 dependent signaling pathways that drive malignant transformation.
Given the devastating nature of HPV- HNSCC and dearth of effective treatment approaches, providing new
insights into the cancer driving molecular mechanisms regulated by PDCD10 and using this knowledge for
developing therapeutic approaches targeting its activity may ultimately improve patient prognosis.
概括
口腔鳞状细胞癌(OCSCC),头颈部鳞状细胞最常见的亚型
癌(HNSCC)是一种毁灭性的疾病,导致了大量的发病率和死亡率。消费
酒精和烟草产品增加了OCSCC的风险。人乳头瘤病毒(HPV)感染的患病率
口咽癌之外的癌症很低,其意义仍然值得商bat。只有少数目标
HPV阴性HNSCC患者(包括许多口腔癌)和
5年的总生存率仍然约为50%。虽然旨在改善风险评估的策略,但
检测和热干预,这些方法受到我们对
HNSCC生物学,特别是在其早期发展中。这是至关重要的,要识别新颖的治疗目标
兴趣。
PDCD10是一种多面蛋白,显示出在几种固体恶性肿瘤中过表达的。据报道
PCDC10调节许多致癌途径,可能有助于肿瘤发生和化学抗性
通过促进细胞增殖,抗凋亡,上皮 - 间质转变和抑制抗肿瘤
免疫反应。最近,有人提出PDCD10参与控制癌症干细胞(CSC)
在乳腺癌和肺癌中维持。与这些观察结果一致,我们的研究表明PDCD10播放
在促进小肠中介导的Wnt/β-catenin介导的干细胞维持中的重要作用。尤其,
以下概述的初步数据为PDCD10在HNSCC中的同等作用提供了有力的证据,并且
表明其表达的上调是肿瘤进程中的重要事件,使PDCD10作为
有价值的预后生物标志物和潜在的治疗靶标。
当PDCD10在几种临床前环境中积极研究,但其在头部中的作用有限
和颈部肿瘤发生。在此提案中,我们将使用基于体内和基于器官的临床前模型,并与
纵向收集的原代人标本的全面生物信息学分析,以评估角色
HNSCC进化和驱动侵袭性肿瘤细胞行为的PDCD10的行为。我们的项目追求三个
独立目标。具体来说:AIM 1将使用具有诱导PDCD10敲除舌的小鼠模型
评估PDCD10耗竭抑制体内口服取消发生的能力; AIM 2将使用人类OCSCC
器官模型评估PDCD10促进CSC生存和自我更新的能力;而AIM 3将
使用纵向收集的口服异型病变和OCSCC的独特现有的RNA-seq数据集
样品以描绘驱动恶性转换的依赖性信号通路的键PDCD10。
鉴于HPV-HNSCC的毁灭性性质和有效治疗方法的死亡,提供了新的
对PDCD10调节的癌症驱动分子机制的见解,并使用这些知识来
开发针对其活动的治疗方法最终可能会改善患者提示。
项目成果
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Evgeny (Eugene) G Izumchenko其他文献
Evgeny (Eugene) G Izumchenko的其他文献
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