Illuminating the Role of Oral Stem Cells in the Development of Oral Squamous Cell Carcinomas
阐明口腔干细胞在口腔鳞状细胞癌发展中的作用
基本信息
- 批准号:9346053
- 负责人:
- 金额:$ 22.8万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-05 至 2018-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdoptedAffectAnimal Cancer ModelBiological AssayBiologyBioluminescenceCancer BiologyCancer ModelCandidate Disease GeneCell divisionCellsChemicalsComplexCritical PathwaysDevelopmentDiagnosticDifferentiated GeneDiseaseEnergy TransferEpigenetic ProcessEpithelialEpitheliumEquilibriumEquipment and supply inventoriesEventEvolutionExhibitsFAT geneFrequenciesGene MutationGenesGeneticGenetic TechniquesGenomicsGoalsGrowthHPV-High RiskHead and Neck Squamous Cell CarcinomaHumanHuman PapillomavirusHuman papillomavirus 16ImageImaging TechniquesInvestmentsKineticsKnowledgeLeadMalignant NeoplasmsMediatingMethodsModelingMusMutateMutationNOTCH1 geneOncoproteinsOralPapillomavirus Transforming Protein E7Pathway interactionsPatient-Focused OutcomesPatientsPharmacotherapyPlayPrincipal InvestigatorProtocols documentationRNA InterferenceReporterResearchResistanceResourcesRoleSignal PathwaySkinSolid NeoplasmStem cellsSurfaceSurvival RateSystemTechniquesTestingThe Cancer Genome AtlasTherapeuticTimeTransgenic MiceTranslatingTumor InitiatorsTumor stageaddictionbasecancer cellcancer recurrencechemical carcinogencombinatorialdimethylbenzanthraceneeffective therapyepigenetic regulationgenetic manipulationgenome sequencinggenome-wideimprovedin uteroin vivoinnovationinsightmalignant mouth neoplasmmortalitymouse modelmouth squamous cell carcinomaneoplastic cellnew therapeutic targetnext generation sequencingnovelnovel therapeuticsoptical imagingoral behaviororal carcinogenesispluripotencyprognostic toolself-renewalsmall hairpin RNAstemstemnesstargeted treatmenttherapeutic targettooltranscription factortreatment strategytumortumor growthtumor initiationtumor progressiontumorigenesis
项目摘要
SUMMARY
Head and neck squamous cell carcinomas (HNSCCs) are the sixth most common cancer worldwide. Despite
decades of research, afflicted patients continue to suffer a staggering ~50% five-year mortality rate. Two
enormous obstacles impede the development of more effective therapies for HNSCC: 1) poor understanding of
the pathways that lead to malignancy and 2) inability to detect tumors early enough. While much has been
learned about the mutational landscape of HNSCCs through next generation sequencing, a tremendous
challenge remains in translating this genomic information into functional relevance. Reliance on animal models
of cancer is critical for separating driver from passenger mutations, to determine pathways that synergize to
promote aggressive tumors, and to develop diagnostic/prognostic tools and therapeutic targets. Unfortunately,
the ability to develop and rapidly test these models is hampered by the large investment of time and resources
required to generate transgenic mice. This proposal addresses these significant knowledge gaps through the
synergistic implementation of cutting-edge genetic and imaging techniques developed by the two principal
investigators. Our long-term goal is to establish high-throughput mouse models of oral cancer that will
elucidate cryptic pathways that promote tumor growth, providing insights into new avenues for therapy. Here,
we adopt our versatile in utero lentiviral transduction technique and novel LumiFluor bioluminescence
resonance energy transfer (BRET) reporter to a validated model of oral cancel, to manipulate underexplored
genetic pathways revealed by genome-wide HNSCC sequencing studies, and visualize how they affect tumor
growth kinetics. Our objective is to understand how self-renewal and differentiation pathways critical to normal
development are co-opted by cancer cells. Our rationale is that two-thirds of HNSCC patient tumors show
mutations in differentiation genes, which is correlated with poor patient survival. Based on our compelling
preliminary studies, we will test the central hypothesis that imbalance between symmetric and asymmetric cell
divisions in tumors—mediated by cytoskeletal control of the spindle orientation machinery and epigenetic
regulation of “stem-ness”—play important roles in HNSCC tumorigenesis. Our Specific Aims are to: 1)
Determine the function of spindle orientation genes in oral carcinogenesis, as this pathway directly regulates
self-renewal/differentiation decisions; and 2) Establish a high-throughput in vivo functional assay for
modulators of tumorigenesis. Both aims use our improved Cre-inducible mouse model of oral cancer based on
a validated, established tumorigenesis protocol driven by high-risk HPV16 E6/E7 and the chemical carcinogen
4-NQO. The proposed research plan is both technically and conceptually innovative. The idea that spindle
orientation is an important regulator of solid tumor growth kinetics is untested, and we possess a unique
toolkit—in utero lentiviral RNAi for rapid genetic manipulations, LumiFluor reporter for advanced imaging, and
an inducible model of HPV+ HNSCCs—that will allow us to make important insights into HNSCC biology.
总结
项目成果
期刊论文数量(0)
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Antonio Luigi Amelio其他文献
Antonio Luigi Amelio的其他文献
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{{ truncateString('Antonio Luigi Amelio', 18)}}的其他基金
Biomarker Approach to Screening for the early detection of HPV-related Oropharyngeal Cancer (BASH OPC)
早期检测 HPV 相关口咽癌的生物标志物筛查方法 (BASH OPC)
- 批准号:
10769204 - 财政年份:2023
- 资助金额:
$ 22.8万 - 项目类别:
Role of CRTC1-MAML2 in Salivary Mucoepidermoid Carcinoma Pathobiology
CRTC1-MAML2 在唾液腺粘液表皮样癌病理学中的作用
- 批准号:
10615108 - 财政年份:2022
- 资助金额:
$ 22.8万 - 项目类别:
Role of CRTC1-MAML2 in Salivary Mucoepidermoid Carcinoma Pathobiology
CRTC1-MAML2 在唾液腺粘液表皮样癌病理学中的作用
- 批准号:
10747770 - 财政年份:2022
- 资助金额:
$ 22.8万 - 项目类别:
Role of CRTC1-MAML2 in Salivary Mucoepidermoid Carcinoma Pathobiology
CRTC1-MAML2 在唾液腺粘液表皮样癌病理学中的作用
- 批准号:
10296299 - 财政年份:2021
- 资助金额:
$ 22.8万 - 项目类别:
Convergence of CREB and MYC Pathways in Oncogenesis.
CREB 和 MYC 通路在肿瘤发生中的融合。
- 批准号:
8930922 - 财政年份:2014
- 资助金额:
$ 22.8万 - 项目类别:
Convergence of CREB and MYC Pathways in Oncogenesis.
CREB 和 MYC 通路在肿瘤发生中的融合。
- 批准号:
8928274 - 财政年份:2014
- 资助金额:
$ 22.8万 - 项目类别:
Convergence of CREB and MYC Pathways in Oncogenesis.
CREB 和 MYC 通路在肿瘤发生中的融合。
- 批准号:
9128558 - 财政年份:2014
- 资助金额:
$ 22.8万 - 项目类别:
Convergence of CREB and MYC Pathways in Oncogenesis.
CREB 和 MYC 通路在肿瘤发生中的融合。
- 批准号:
8544427 - 财政年份:2012
- 资助金额:
$ 22.8万 - 项目类别:
Convergence of CREB and MYC Pathways in Oncogenesis.
CREB 和 MYC 通路在肿瘤发生中的融合。
- 批准号:
8241509 - 财政年份:2012
- 资助金额:
$ 22.8万 - 项目类别:
Characterizing the Role of MYC-MAX Complexes in TORC1/MAML2-mediated Oncogenesis
表征 MYC-MAX 复合物在 TORC1/MAML2 介导的肿瘤发生中的作用
- 批准号:
7540099 - 财政年份:2008
- 资助金额:
$ 22.8万 - 项目类别:
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