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概要
越来越多的数据表明,表型和转录可塑性是重要的特征,有助于
癌细胞的转移进展、向性和对治疗的反应。我们和其他人提供了
令人信服的证据表明,在原发性黑色素瘤中存在瘤内异质性,这表明它是一种早期的恶性肿瘤。
对肿瘤发生很重要。此外,最近的报告表明,黑色素瘤细胞可以转换,
表型状态之间的关系,其中一些与更具侵略性的生物学相关,暗示着
转录可塑性在这种表型变异。然而,肿瘤细胞内在特征的演变
与黑色素瘤进展相关的疾病仍然在很大程度上未被表征。这些研究评估了
涉及黑色素瘤转移的转录组学和表观遗传学特征通常集中在个体
分子特征局限于特定的细胞群,并且未能整合转移性肿瘤。
整个过程。我们假设,转录异质性的出现,引起不同的
原发性皮肤黑色素瘤的细胞状态是驱动早期转移性播散的关键步骤,
具有特定的转录程序,具有大部分的转移潜力。项目1的目标是
研究转移的分子驱动因素的时间和功能,
转录异质性和细胞状态的转移轨迹。我们将在新的基因
工程小鼠模型,反映人类疾病以及临床注释的患者样品。使用
一种创新的方法,整合了遗传条形码,单细胞RNA测序,空间转录组学,
和高度多重免疫组织化学,我们将评估特定转录细胞状态的存在,
在小鼠和人原发性黑色素瘤中,并使用动物模型评估它们对转移潜能的影响。
模型和统计学与已知患者结局相关(目标1)。然后我们将研究
通过测试单个候选基因对它们的出现的贡献,
维持及其对转移潜力的影响(目的2)。
本研究项目将利用核心B和C的病理、技术和分析资源。
与项目2和3的整合将剖析黑色素瘤细胞之间不断发展的双向串扰,
它们的微环境最终导致肿瘤转移了解特定细胞的贡献
早期传播的潜在状态和分子程序可以提高我们对患者进行亚分类的能力
根据转移风险诊断原发性黑色素瘤,并确定哪些患者受益最大
加强监测或辅助治疗。我们的研究也可能为新的
预防或靶向转移的治疗方法。最后,这项研究的结果可能适用于其他
其中早期播散导致转移潜能增加和预后更差的肿瘤类型。
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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