NYULH Metastasis Research Network Center (NYULH MetNet Center)

总体总结 传统观点认为癌症是一种以遗传为主的疾病，是以循序渐进、线性的方式进行的， 已经放弃了一种理解，即肿瘤的进展涉及一组多方面的肿瘤细胞--固有的和 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。 发现了当地环境中的不同细胞群如何在不同的环境中驱动转移行为 肿瘤进展的各个阶段。仅有毫米厚的原发黑色素瘤可扩散至淋巴结。 和远处的器官。这一临床特征表明，肿瘤细胞从原发部位流出的时间较早。 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 肿瘤进展的最早阶段。我们的中心假设是黑色素瘤的转移是由 肿瘤细胞固有特征的组合及其与微环境隔间的相互作用 控制区域引流淋巴结内的早期传播和免疫逃逸。为了测试这一点 假设，我们提出了三个相互关联的项目，由三个核心支持，这些核心将共同构建一个内部- 早期肿瘤微环境中关键隔室的深度转录和细胞图谱 黑色素瘤扩散，在小鼠模型和患者生物标本中。成功完成这些任务 项目将识别这些隔间中驱动和维持的基因和转录程序 肿瘤形成适应和最终的转移性传播。我们的目标是：1.绘制细胞和 原发性黑色素瘤的分子进化及其局部和区域微环境 驱动肿瘤非线性进展的“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体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，调动系统免疫 监测，并改善患者的预后；以及4.利用获得的信息来定义新的生物标志物 黑色素瘤转移的可能性。我们希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管理早期疾病的治疗策略。我们的方法可以 作为研究早期肿瘤进展的路线图，在细胞、空间和时间上达到前所未有的水平 决议。它将提供肿瘤微环境内相互作用的全面图景 影响肿瘤细胞行为并使宿主接受转移的肿瘤引流淋巴结节 散开。我们将利用我们研究团队的互补和协同专业知识，建立一个 生产性协作的记录，我们的新的基因工程小鼠模型，早期总结 人类黑色素瘤的进展，以及我们获得高质量的、经过临床注释的患者样本的途径 在一个前瞻性的临床病理数据库中登记了4700名患者。知识的范围和可扩展性 Gain将为转移研究网络的其他站点提供服务。

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.