Project 3: The Evolving Role of Regional Lymph Nodes in Melanoma Progression

项目 3：区域淋巴结在黑色素瘤进展中的演变作用

• 批准号: 10414446
• 负责人: Amanda W. Lund
• 金额: $ 37.13万
• 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/10414446
• 关键词: Archives; Automobile Driving; Biological Markers; Biology; Biopsy; Cell Line; Cells; Clinical; Clinical Management; Complex; Critical Pathways; Data; Diagnostic Neoplasm Staging; Disease; Disease Outcome; Distant; Distant Metastasis; Electronic Medical Records and Genomics Network; Event; Evolution; Excision; Exhibits; Freezing; Generations; Goals; Human; Image; Immune; Immunity; Immunologic Markers; Immunologic Surveillance; Immunologics; Immunosuppression; Interferon Type I; Interferons; Investigation; Knockout Mice; Knowledge; Lymph; Lymph Node Dissections; Lymph Node Subcapsular Sinus; Lymph Node Tissue; Lymphatic Endothelial Cells; Malignant Neoplasms; Maps; Melanoma Cell; Metastatic Neoplasm to Lymph Nodes; Modeling; Molecular; Mus; Neighborhoods; Neoplasm Metastasis; Operative Surgical Procedures; Organ; Outcome; Patient risk; Patient-Focused Outcomes; Patients; Phenotype; Recurrence; Regional Disease; Research; Research Personnel; Resources; Rest; Retrospective cohort; Role; Sentinel Lymph Node; Signal Transduction; Site; Solid Neoplasm; Staging; Systemic disease; Testing; Time; Tissues; Tumor Biology; Tumor Immunity; Validation; Work; base; cancer cell; clinical care; clinically relevant; cohort; computational pipelines; computerized tools; draining lymph node; experimental study; high dimensionality; improved; innovation; interest; liquid crystal polymer; lymph nodes; malignant breast neoplasm; melanoma; melanoma biomarkers; melanomagenesis; mouse model; multiplexed imaging; neoplastic cell; novel; patient stratification; patient subsets; personalized strategies; prognostic; programs; risk stratification; transcriptomics; treatment response; tumor; tumor immunology; tumor progression; tumor-immune system interactions

PROJECT 3 SUMMARY Cancers commonly spread from their primary site and colonize regional lymph nodes (LNs), representing a hallmark of progression and a key parameter for staging. The prognostic impact of LN metastasis and utility of complete LN dissection in patients with micrometastatic LN disease, however, varies between solid tumor types and patient subsets. The clinical observation that removal of micrometastatic LN disease does not by definition improve survival has highlighted a gap in our understanding of regional LN metastasis and calls into question the simple model of sequential metastasis. Given that LNs are both an early site of metastasis and immunological organs, the interplay between dissemination and immunity may be critical to understanding how LNs impact outcome. Here we will investigate the biology of tumor-draining LNs to ask whether regional draining LNs act as an educational site that ultimately shifts the systemic macroenvironment to favor distant tumor outgrowth. In this proposal we test the hypothesis that sentinel LNs undergo a cascade of cellular and molecular events that prime the host to be receptive to tumor progression. To test this hypothesis, we will build an unbiased, temporally, and spatially resolved map of regional draining LNs. This will enable us to identify clinically relevant mechanisms that determine outcome by integrating a deep, mechanistic understanding of lymphatic and LN biology together with high-dimensional imaging and novel, computational tools in mice and humans. To build this map, we will leverage fresh frozen LNs from surgical cases, archived, FFPE matched primary and metastasis pairs, and a clinically relevant mouse model, and determine the early changes that support tumor cell seeding and the melanoma cell states that first arrive in LNs (Aim 1). We will further test causal programs, including type I interferon signaling, that may functionally initiate this tumor permissive state and install local mechanisms of adaptive immune suppression that limit systemic immune surveillance and thereby distant metastasis (Aim 2). Finally, we will leverage the extensive resource and expertise of Core B to investigate the utility of immune markers to stratify patient risk from archived sentinel LN tissue and thereby predict recurrence in Stage II and III melanoma patients (Aim 3). The work we propose here promises to significantly reimagine the role of the sentinel LN in systemic melanoma progression. This conceptual shift may inform personalized strategies to manage local disease and thereby mobilize anti-tumor immunity and systemic tumor control across solid tumor types and identify immune-based LN features to stratify risk for recurrence in melanoma and guide clinical care. The resources and knowledge generated through this proposal will be made publicly accessible through NYULH MetNet Center Cores B and C, which will enable extension of these observations to other solid tumor types (e.g. breast cancer) through the broader Metastasis Research Network and therefore enable a significantly expanded understanding of LN metastasis and progression.

项目3摘要 癌症通常从其主要部位传播，并定居区域淋巴结（LNS），代表A 进展的标志和分期的关键参数。 LN转移和实用性的预后影响 然而，微转移LN疾病患者的完全LN解剖在实体瘤类型之间有所不同 和患者子集。根据定义，去除微转移LN疾病的临床观察结果 改善生存已经强调了我们对区域LN转移的理解的差距，并引起了质疑 顺序转移的简单模型。鉴于LN既是转移的早期部位又是免疫学的早期部位 器官，传播与免疫之间的相互作用对于理解LNS的影响可能至关重要 结果。在这里，我们将研究肿瘤排出的LN的生物学，以询问区域排水LNS是否起作用 最终将系统性宏观环境转变为有利于远处肿瘤生长的教育地点。 在此提案中，我们检验了哨兵LNS经历一系列细胞和分子事件的假设 那个宿主可以接受肿瘤进展。为了检验这一假设，我们将建立一个公正的， 在时间和空间上解决区域排水LN的图。这将使我们能够确定临床上相关的 通过整合对淋巴和LN的深刻的机械理解来确定结果的机制 生物学以及小鼠和人类的高维成像和新颖的计算工具。建造 这张地图，我们将利用手术病例中的新鲜冷冻LN，归档的FFPE匹配和转移 成对和临床相关的小鼠模型，并确定支持肿瘤细胞播种的早期变化 黑色素瘤细胞首先到达LNS（AIM 1）。我们将进一步测试因果计划，包括类型 我干涉信号，这可能在功能上启动这种肿瘤允许状态并安装局部机制 适应性免疫抑制，从而限制全身免疫监测并因此转移（AIM 2）。 最后，我们将利用核心B的广泛资源和专业知识来调查免疫的实用性 标记以从存档的哨兵组织中分层风险，从而预测II和III期的复发 黑色素瘤患者（AIM 3）。我们在这里提出的工作有望显着重新构想前哨的作用 LN全身性黑色素瘤进展。这种概念上的转变可能会为管理本地的个性化策略提供信息 疾病，从而动员实体瘤类型的抗肿瘤免疫和全身性肿瘤控制 确定基于免疫的LN特征，以分层黑色素瘤复发的风险并引导临床护理。 通过本提案产生的资源和知识将通过NYULH公开访问 Metnet中心核B和C，这将使这些观测值扩展到其他实体瘤类型（例如 乳腺癌）通过更广泛的转移研究网络，因此可以显着扩展 了解LN转移和进展。