Project 1: Tumor Cell Intrinsic Determinants of Early Dissemination in Melanoma
项目1:黑色素瘤早期播散的肿瘤细胞内在决定因素
基本信息
- 批准号:10414444
- 负责人:
- 金额:$ 32.89万
- 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:2022-09-15 至 2027-07-31
- 项目状态:未结题
- 来源:
- 关键词:Adjuvant TherapyAnimal ModelAnoikisAutomobile DrivingBar CodesBehaviorBiologyCandidate Disease GeneCell modelCellsCessation of lifeClinicalCutaneous MelanomaDataDermalDevelopmentDiagnosisEpigenetic ProcessEvolutionExhibitsGene Expression ProfileGeneticGenetic EngineeringGenetic TranscriptionGenetically Engineered MouseGoalsHeterogeneityHumanImmunohistochemistryIndividualInformation DisseminationInvadedLaboratoriesLightLinkMaintenanceMalignant NeoplasmsMelanoma CellMesenchymalMetastatic MelanomaMetastatic toModelingMolecularMonitorMusNeoplasm MetastasisNeural CrestNuclear ReceptorsOutcomeOutputPathogenesisPathologicPatient-Focused OutcomesPatientsPhenotypePopulationPrimary NeoplasmPrognostic MarkerPropertyProtein IsoformsReportingResearchResearch Project GrantsResectedResourcesRiskSamplingSignal TransductionSiteTestingTissuesTranscriptTranscriptional RegulationTropismTumor stageVariantapoAI regulatory protein-1cancer celldata integrationhigh riskhuman diseasehuman modelimprovedinnovationmelanomametastatic processmigrationmillimetermouse modelneoplastic cellnovelnovel therapeutic interventionpatient prognosispreventprogramsprospectivescreeningsingle-cell RNA sequencingtranscriptomicstreatment responsetumortumor heterogeneitytumorigenesistumorigenic
项目摘要
PROJECT 1 SUMMARY
Increasing data suggest that phenotypic and transcriptional plasticity are important features that contribute to
metastatic progression, tropism, and response to therapy of cancer cells. We and others have provided
compelling evidence that intratumoral heterogeneity exists in primary melanomas, suggesting it is an early
feature important for tumorigenesis. Further, recent reports demonstrate that melanoma cells can switch
between phenotypic states, some of which are associated with more aggressive biology, implicating
transcriptional plasticity in this phenotypic variation. However, the evolution of tumor cell intrinsic features
associated with melanoma progression remains largely uncharacterized. The studies that have evaluated
transcriptomic and epigenetic features involved in melanoma metastasis have typically focused on individual
molecular features restricted to a specific cell population, and have fallen short of integrating the metastatic
process as a whole. We hypothesize that emergence of transcriptional heterogeneity that gives rise to distinct
cell states in primary cutaneous melanoma is a critical step driving early metastatic dissemination, and that cells
with a specific transcriptional program harbor the bulk of metastatic potential. The goal of Project 1 is to
investigate the timing and function of molecular drivers of metastasis, the emergence and evolution of
transcriptional heterogeneity and metastatic trajectories of cell states. We will do this in novel genetically
engineered mouse models that reflect human disease as well as in clinically annotated patient samples. Using
an innovative approach that integrates genetic bar coding, single cell RNA sequencing, spatial transcriptomics,
and highly-multiplexed immunohistochemistry, we will assess the presence of specific transcriptional cell states
within murine and human primary melanomas, and assess their influence on metastatic potential using animal
models and statistical correlates to known patient outcomes (Aim 1). We will then study the mechanisms driving
these transcriptional cell states by testing the contribution of individual candidate genes to their emergence and
maintenance and their impact on metastatic potential (Aim 2).
This research project will leverage the pathological, technological, and analytical resources of Cores B and C.
Integration with Projects 2 and 3 will dissect the evolving, bidirectional crosstalk between melanoma cells and
their microenvironment that culminates in a metastasizing tumor. Understanding the contribution of specific cell
states and the molecular programs underlying early dissemination can improve our ability to subclassify patients
diagnosed with primary melanoma by their risk of metastasis and identify those patients who could benefit most
from increased surveillance or adjuvant therapies. Our studies might also provide a rationale for novel
therapeutic approaches to prevent or target metastasis. Finally, findings from this research may apply to other
tumor types wherein early dissemination results on increased metastatic potential and worse outcomes.
项目1总结
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)
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Eva Hernando其他文献
Eva Hernando的其他文献
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{{ truncateString('Eva Hernando', 18)}}的其他基金
Developing new therapeutic strategies for brain metastasis
开发脑转移的新治疗策略
- 批准号:
10578405 - 财政年份:2023
- 资助金额:
$ 32.89万 - 项目类别:
NYULH Metastasis Research Network Center - Admin Supplement
NYULH 转移研究网络中心 - 管理补充
- 批准号:
10867093 - 财政年份:2022
- 资助金额:
$ 32.89万 - 项目类别:
Project 1: Tumor Cell Intrinsic Determinants of Early Dissemination in Melanoma
项目1:黑色素瘤早期播散的肿瘤细胞内在决定因素
- 批准号:
10705072 - 财政年份:2022
- 资助金额:
$ 32.89万 - 项目类别:
NYULH Metastasis Research Network Center (NYULH MetNet Center)
NYULH 转移研究网络中心(NYULH MetNet 中心)
- 批准号:
10414442 - 财政年份:2022
- 资助金额:
$ 32.89万 - 项目类别:
Defining epigenetic regulators of tumor heterogeneity and metastasis in melanoma
定义黑色素瘤肿瘤异质性和转移的表观遗传调节因子
- 批准号:
10659255 - 财政年份:2022
- 资助金额:
$ 32.89万 - 项目类别:
Defining epigenetic regulators of tumor heterogeneity and metastasis in melanoma
定义黑色素瘤肿瘤异质性和转移的表观遗传调节因子
- 批准号:
10512423 - 财政年份:2022
- 资助金额:
$ 32.89万 - 项目类别:
NYULH Metastasis Research Network Center (NYULH MetNet Center)
NYULH 转移研究网络中心(NYULH MetNet 中心)
- 批准号:
10705068 - 财政年份:2022
- 资助金额:
$ 32.89万 - 项目类别:
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