NYULH Metastasis Research Network Center - Admin Supplement

NYULH 转移研究网络中心 - 管理补充

• 批准号: 10867093
• 负责人: Eva Hernando
• 金额: $ 5.09万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 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/10867093
• 关键词: Behavior; Cells; Clinical; Collaborations; Complex; Computational Biology; Data; Databases; Dermal; Development; Disease; Distant; Environment; Evolution; Financial Support; Frequencies; Genes; Genetic; Genetic Diseases; Genetic Transcription; Genetically Engineered Mouse; Genomics; Heterogeneity; Human; Immune Evasion; Immune response; Immunologic Surveillance; Infrastructure; Institution; Intercept; Knowledge; Link; Malignant - descriptor; Malignant Neoplasms; Maps; Mediating; Methods; Modeling; Molecular; Molecular Evolution; Neoplasm Metastasis; Non-Malignant; Organ; Output; Patient Care; Patient-Focused Outcomes; Patients; Population; Productivity; Recurrence; Research; Research Personnel; Resources; Risk; Sampling; Signal Transduction; Site; Skin; System; Testing; Therapeutic; Therapeutic Intervention; Thick; Tissues; Tumor stage; biomarker identification; cancer type; cell behavior; cell type; clinically relevant; computer framework; draining lymph node; epigenetic regulation; improved; innovation; lymph nodes; melanoma; melanoma biomarkers; millimeter; mouse genetics; mouse model; multidisciplinary; neoplastic cell; new therapeutic target; novel; novel therapeutics; participant enrollment; permissiveness; prevent; programs; prospective; stem cell biology; survival outcome; synergism; temporal measurement; transcriptomics; tumor; tumor immunology; tumor microenvironment; tumor progression; tumorigenic

OVERALL SUMMARY Conventional views of cancer as a predominantly genetic disease that proceeds in a step-wise, linear manner, have ceded to an understanding that tumor progression involves a multifaceted set of tumor cell-intrinsic and micro-environmental adaptations that co-evolve dynamically and non-linearly. However, much remains to be discovered about how different cell populations in the local environment drive metastatic behavior at different stages of tumor progression. Primary melanomas that are only millimeters thick can disseminate to lymph nodes and distant organs. This clinical feature suggests that egress of tumor cells from a primary site occurs early in melanoma development making melanoma an exceptional model to study these dynamic adaptations during the earliest stages of tumor progression. Our central hypothesis is that melanoma metastasis is driven by a combination of tumor cell–intrinsic features and interactions with micro-environmental compartments that govern early dissemination and immune evasion in the regional draining lymph nodes. To test this hypothesis, we propose three inter-related projects, supported by three cores that will collectively build an in- depth transcriptional and cellular map of critical compartments in the tumor microenvironment during early melanoma dissemination, in both mouse models and patient biospecimens. Successful completion of these projects will identify genes and transcriptional programs within those compartments that drive and maintain tumorigenic adaptations and ultimately metastatic dissemination. Our aims are to: 1. Map the cellular and molecular evolution of primary melanomas and their local and regional microenvironments to identify critical ‘switches’ that drive non-linear tumor progression; 2. Mechanistically dissect the emergence and functional relevance of transcriptionally defined cell state heterogeneity of malignant and non-malignant cell populations; 3. Identify novel therapeutic vulnerabilities to intercept early dissemination, mobilize systemic immune surveillance, and improve patient outcomes; and 4. Leverage the information gained to define new biomarkers of melanoma metastasis. We expect that knowledge generated through our approach may define new biomarkers of melanoma metastasis and therapeutic strategies to manage early disease. Our approach can serve as a roadmap to study early tumor progression at an unprecedented level of cellular, spatial and temporal resolution. It will provide a comprehensive picture of interactions both within the tumor microenvironment and tumor draining lymph nodes that influence tumor cell behavior and condition the host to be receptive to metastatic spread. We will leverage the complementary and synergistic expertise of our research team with an established record of productive collaboration, our novel genetically engineered mouse model that recapitulates early progression of human melanoma, and our access to high quality, clinically annotated patient samples from over 4,700 patients enrolled in a prospective clinicopathological database. The scope and scalability of the knowledge gained will serve other sites of the Metastasis Research Network.

总体总结 传统观点认为癌症是一种以逐步、线性方式进展的主要遗传性疾病， 已经承认肿瘤进展涉及多方面的肿瘤细胞内在和 动态和非线性共同进化的微环境适应然而，还有很多事情要做。 发现局部环境中的不同细胞群如何驱动不同部位的转移行为 仅几毫米厚的原发性黑色素瘤可扩散至淋巴结。 这一临床特征表明肿瘤细胞从原发部位的流出发生在早期。 黑色素瘤的发展使黑色素瘤成为研究这些动态适应的特殊模型 我们的中心假设是黑色素瘤转移是由肿瘤进展驱动的。 肿瘤细胞固有特征和与微环境区室相互作用的组合 控制区域引流淋巴结的早期传播和免疫逃避。 假设，我们提出了三个相互关联的项目，由三个核心支持，共同构建一个内部- 早期肿瘤微环境中关键区室的深度转录和细胞图 小鼠模型和患者生物样本中的黑色素瘤传播成功完成。 项目将识别这些区室中驱动和维持的基因和转录程序 我们的目标是： 1. 绘制细胞和细胞图谱。 原发性黑色素瘤及其局部和区域微环境的分子进化，以确定关键的 驱动非线性肿瘤进展的“开关”；2.从机制上剖析肿瘤的出现和功能 恶性和非恶性细胞群的转录定义的细胞状态异质性的相关性； 3. 识别新的治疗漏洞以拦截早期传播，动员全身免疫 监测，并改善患者的治疗效果；以及 4. 利用获得的信息来定义新的生物标志物 我们期望通过我们的方法产生的知识可以定义新的。 黑色素瘤转移的生物标志物和控制早期疾病的治疗策略可以。 作为在前所未有的细胞、空间和时间水平上研究早期肿瘤进展的路线图 它将提供肿瘤微环境内相互作用的全面图景。 肿瘤引流淋巴结，影响肿瘤细胞行为并调节宿主接受转移 我们将利用我们研究团队的互补和协同专业知识与既定的经验。 富有成效的合作记录，我们的新型基因工程小鼠模型重现了早期 人类黑色素瘤的进展，以及我们从多个国家获得高质量、经过临床注释的患者样本 前瞻性临床病理学数据库纳入了 4,700 名患者 知识的范围和可扩展性。 获得的成果将服务于转移研究网络的其他站点。