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癌细胞的转移进展、趋向性和治疗反应。我们和其他人提供了令人信服的证据表明，原发性黑色素瘤存在瘤内异质性，表明它是一种早期的黑色素瘤。对肿瘤发生很重要的特征。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，其中一些与更具攻击性的生物学相关，这意味着这种表型变异的转录可塑性。然而，肿瘤细胞内在特征的进化与黑色素瘤进展的相关性在很大程度上仍然未知。已评估的研究黑色素瘤转移涉及的转录组学和表观遗传学特征通常集中于个体分子特征仅限于特定细胞群，并且无法整合转移性细胞整个过程。我们假设转录异质性的出现导致了不同的原发性皮肤黑色素瘤的细胞状态是驱动早期转移扩散的关键步骤，并且细胞具有特定转录程序的细胞具有大量的转移潜力。项目 1 的目标是研究转移分子驱动因素的时间和功能、转移的出现和演变细胞状态的转录异质性和转移轨迹。我们将在小说基因中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。使用一种创新方法，集成了遗传条形码、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类原发性黑色素瘤中，并使用动物评估它们对转移潜力的影响模型和统计与已知的患者结果相关（目标 1）。然后我们将研究驱动机制这些转录细胞状态通过测试单个候选基因对其出现的贡献和维持及其对转移潜能的影响（目标 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和它们的微环境最终形成转移性肿瘤。了解特定细胞的贡献早期传播的状态和分子程序可以提高我们对患者进行细分的能力根据转移风险诊断原发性黑色素瘤，并确定哪些患者最能受益来自加强监测或辅助治疗。我们的研究也可能为小说提供理论依据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传播导致转移潜力增加和结果更差的肿瘤类型。