NYULH Metastasis Research Network Center - Admin Supplement

总体汇总 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， 已经放弃了一种理解，即肿瘤进展涉及一组多方面的肿瘤细胞-内在的， 微环境适应，共同演变动态和非线性。然而， 发现了当地环境中不同的细胞群如何在不同的时间驱动转移行为， 肿瘤进展的阶段。只有毫米厚的原发性黑色素瘤可以扩散到淋巴结 远器官。这一临床特征表明，肿瘤细胞从原发部位的逃逸发生在早期， 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， 肿瘤进展的最早阶段。我们的中心假设是，黑色素瘤转移是由一种 肿瘤细胞内在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中的早期传播和免疫逃避。为了验证这一 假设，我们提出了三个相互关联的项目，由三个核心支持，将共同建立一个在- 在早期肿瘤微环境中关键区室的深度转录和细胞图谱 在小鼠模型和患者生物样本中，黑色素瘤传播。成功完成这些 项目将确定基因和转录程序在这些隔间，驱动和维持 致瘤适应和最终的转移性传播。我们的目标是：1.映射蜂窝和 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.机械地剖析了 恶性和非恶性细胞群体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，并改善患者的结果;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 作为一个路线图，研究早期肿瘤进展在前所未有的水平，细胞，空间和时间 分辨率它将提供肿瘤微环境内相互作用的全面图片， 肿瘤引流淋巴结，其影响肿瘤细胞行为并使宿主接受转移性淋巴结 传播.我们将利用我们的研究团队的互补和协同专业知识， 富有成效的合作记录，我们的新的基因工程小鼠模型，重演早期 人类黑色素瘤的进展，以及我们从超过1000名患者中获得高质量的临床注释患者样本， 4，700例患者入组前瞻性临床病理学数据库。知识的范围和可扩展性 gained将服务于转移研究网络的其他网站。

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.