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: 10705088
• 负责人: Amanda W. Lund
• 金额: $ 36.57万
• 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/10705088
• 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; Education; 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; Localized Disease; 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; 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; outcome disparities; patient stratification; patient subsets; permissiveness; personalized strategies; prognostic; programs; risk stratification; spatial integration; transcriptomics; treatment response; tumor; tumor immunology; tumor initiation; 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 癌症通常从原发部位扩散并定植区域淋巴结 (LN)，这代表着 进展的标志和分期的关键参数。淋巴结转移的预后影响及其效用 然而，微转移性淋巴结疾病患者的完整淋巴结清扫因实体瘤类型而异 和患者子集。根据定义，微转移淋巴结疾病的切除并不意味着临床观察 提高生存率凸显了我们对区域性淋巴结转移的理解存在差距，并引发了质疑 序贯转移的简单模型。鉴于淋巴结既是转移的早期部位，又是免疫学部位 器官，传播和免疫之间的相互作用可能对于理解 LN 如何影响至关重要 结果。在这里，我们将研究肿瘤引流淋巴结的生物学，以询问区域引流淋巴结是否充当 一个最终改变系统宏观环境以有利于远处肿瘤生长的教育网站。 在本提案中，我们测试了前哨 LN 经历一系列细胞和分子事件的假设 使宿主能够接受肿瘤的进展。为了检验这个假设，我们将建立一个无偏见的、 区域排水 LN 的时间和空间解析图。这将使我们能够识别临床相关的 通过整合对淋巴管和淋巴结的深入、机械的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 在这张图上，我们将利用来自手术病例、存档、FFPE 匹配的原发灶和转移灶的新鲜冷冻淋巴结 配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淋巴结（目标 1）。我们将进一步测试因果程序，包括类型 I 干扰素信号传导，可能在功能上启动这种肿瘤许可状态并安装局部机制 适应性免疫抑制限制全身免疫监视，从而限制远处转移（目标 2）。 最后，我们将利用 Core B 的广泛资源和专业知识来研究免疫的效用 标记物可根据存档的前哨淋巴结组织对患者风险进行分层，从而预测 II 期和 III 期复发 黑色素瘤患者（目标 3）。我们在此提出的工作有望显着重新构想哨兵的角色 系统性黑色素瘤进展中的 LN。这种概念上的转变可能会为管理本地化的个性化策略提供信息。 疾病，从而调动抗肿瘤免疫和跨实体瘤类型的全身肿瘤控制 识别基于免疫的淋巴结特征，对黑色素瘤复发风险进行分层并指导临床护理。 通过该提案产生的资源和知识将通过 NYULH 公开获取 MetNet 中心核心 B 和 C，这将使这些观察结果扩展到其他实体瘤类型（例如实体瘤）。 乳腺癌）通过更广泛的转移研究网络，因此能够显着扩大 了解淋巴结转移和进展。