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
• 负责人: Eva Hernando
• 金额: $ 165.45万
• 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/10705068
• 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.

总结 癌症的常规观点是以逐步，线性的方式进行的主要遗传疾病 已经理解，肿瘤进展涉及一组肿瘤细胞中的一组 动态和非线性共同发展的微环境适应。但是，还有很多事情要 发现当地环境中不同的细胞群体如何驱动不同的转移性行为 肿瘤进展的阶段。仅毫米厚的原发性黑色素瘤可以传播到淋巴结 和遥远的器官。该临床特征表明，肿瘤细胞从主要部位的出口发生早期 黑色素瘤的发育使黑色素瘤成为研究这些动态适应期间的特殊模型 肿瘤进展的最早阶段。我们的中心假设是黑色素瘤转移是由 肿瘤细胞 - 内膜特征和与微环境室的相互作用的结合 控制区域排水淋巴结中的早期传播和免疫进化。测试这个 假设，我们提出了三个相互关联的项目，并得到了三个核心的支持，这些核心将共同建立一个内部 早期肿瘤微环境中关键隔室的深度转录和细胞图 在小鼠模型和患者生物测量中，黑色素瘤传播。这些成功完成 项目将在那些驱动和维护的隔室内识别基因和转录程序 肿瘤的适应性和最终转移性传播。我们的目的是：1。映射细胞和 原发性黑色素瘤及其局部和区域微环境的分子进化以鉴定关键 驱动非线性肿瘤进展的“开关”； 2。机械剖析出现和功能 转录定义的恶性和非恶性细胞群体的细胞状态异质性的相关性； 3。确定新的治疗脆弱性以拦截早期传播，动员全身免疫 监视并改善患者预后；和4。利用获得的信息来定义新的生物标志物 黑色素瘤转移。我们希望通过我们的方法产生的知识可能定义新的知识 黑色素瘤转移和治疗早期疾病的治疗策略的生物标志物。我们的方法可以 作为在前所未有的细胞，空间和临时水平上研究早期肿瘤进展的路线图 解决。它将在肿瘤微环境和 影响肿瘤细胞行为和条件宿主接受转移性的肿瘤排泄淋巴结 传播。我们将利用研究团队的完整性和协同专业知识 生产性合作的记录，我们的新型基因工程鼠标模型，该模型早日概括 人类黑色素瘤的进展，以及我们获得高质量的临床注释的患者样本 有4,700名患者参加了前瞻性临床病理数据库。知识的范围和可扩展性 获得的将服务于转移研究网络的其他站点。