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：
Eva Hernando
金额：
$ 32.89万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
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：
https://reporter.nih.gov/project-details/10414444
关键词：
Adjuvant Therapy Animal Model Anoikis Automobile Driving Bar Codes Behavior Biology Candidate Disease Gene Cell model Cells Cessation of life Clinical Cutaneous Melanoma Data Dermal Development Diagnosis Epigenetic Process Evolution Exhibits Gene Expression Profile Genetic Genetic Engineering Genetic Transcription Genetically Engineered Mouse Goals Heterogeneity Human Immunohistochemistry Individual Information Dissemination Invaded Laboratories Light Link Maintenance Malignant Neoplasms Melanoma Cell Mesenchymal Metastatic Melanoma Metastatic to Modeling Molecular Monitor Mus Neoplasm Metastasis Neural Crest Nuclear Receptors Outcome Output Pathogenesis Pathologic Patient-Focused Outcomes Patients Phenotype Population Primary Neoplasm Prognostic Marker Property Protein Isoforms Reporting Research Research Project Grants Resected Resources Risk Sampling Signal Transduction Site Testing Tissues Transcript Transcriptional Regulation Tropism Tumor stage Variant apoAI regulatory protein-1 cancer cell data integration high risk human disease human model improved innovation melanoma metastatic process migration millimeter mouse model neoplastic cell novel novel therapeutic intervention patient prognosis prevent programs prospective screening single-cell RNA sequencing transcriptomics treatment response tumor tumor heterogeneity tumorigenesis tumorigenic

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摘要越来越多的数据表明，表型和转录可塑性是有助于转移性进展，对流和对癌细胞治疗的反应。我们和其他人提供了令人信服的证据表明，原发性黑色素瘤中存在肿瘤内异质性，这表明这是早期的特征对于肿瘤发生很重要。此外，最近的报告表明黑色素瘤细胞可以切换在表型状态之间，其中一些与更具侵略性的生物学相关，这意味着这种表型变化中的转录可塑性。但是，肿瘤细胞固有特征的演变与黑色素瘤进展相关的基本上仍然没有特征。评估的研究黑色素瘤转移涉及的转录组和表观遗传特征通常集中在个体上分子特征仅限于特定的细胞群，并且缺少整合转移性整个过程。我们假设转录异质性的出现引起了不同原发性皮肤瘤中的细胞态是驱动早期转移性传播的关键步骤，并且细胞特定的转录程序具有大部分转移潜力。项目1的目标是研究转移分子驱动因素的时间和功能，出现和演变细胞态的转录异质性和转移轨迹。我们将在遗传上做到这一点反映人类疾病以及临床注释的患者样本的工程小鼠模型。使用一种创新的方法，该方法整合了遗传条编码，单细胞RNA测序，空间转录组学，和高度多重的免疫组织化学，我们将评估特定转录细胞态的存在在鼠和人类原发性黑色素瘤中，并评估它们使用动物对转移性潜力的影响模型和统计与已知的患者结局相关（AIM 1）。然后，我们将研究驾驶机制这些转录细胞状态通过测试个别候选基因对其出现的贡献，并维护及其对转移潜力的影响（AIM 2）。该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他们的微环境最终在转移肿瘤中。了解特定细胞的贡献各州和早期传播基础的分子程序可以提高我们对患者分类的能力因其转移风险而被诊断出患有原发性黑色素瘤，并确定那些可以使大多数受益的患者来自增加的监视或辅助疗法。我们的研究也可能为新颖的理由提供理由预防或靶向转移的治疗方法。最后，这项研究的发现可能适用于其他肿瘤类型，其中早期传播导致转移性潜力增加和结果较差。