Systems Biology of Tumor-Immune-Stromal Interactions in Metastatic Progression

转移进展中肿瘤-免疫-基质相互作用的系统生物学

• 批准号: 10729464
• 负责人: EDGAR G. ENGLEMAN
• 金额: $ 191.91万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10729464
• 关键词: Adaptive Immune System; Address; Advanced Development; Affect; Anatomy; Archives; Area; Binding; Biological; Biological Markers; Cancer Etiology; Cancer Patient; Cells; Cessation of life; Clinical; Collaborations; Communities; Complex; Computer Analysis; Computing Methodologies; Data; Data Set; Dedications; Development; Disease; Distant; Distant Metastasis; Ensure; Event; Funding; Generations; Genomics; Goals; Head and Neck Cancer; Homeostasis; Human; Image; Imaging technology; Immune; Immune Tolerance; Immune system; Immunology; Immunosuppression; In Situ; Invaded; Kinetics; Knowledge; Lung Adenocarcinoma; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Mediator; Metastatic Neoplasm to Lymph Nodes; Methodology; Methods; Mus; Nature; Neoplasm Metastasis; Outcome; Patients; Pilot Projects; Population; Predisposition; Primary Neoplasm; Process; Proteomics; Records; Research; Research Personnel; Research Project Grants; Resource Sharing; Role; Sampling; Series; Site; Solid; Solid Neoplasm; Stromal Cells; Stromal Neoplasm; System; Systems Biology; Technology; Therapeutic; Tissues; Tumor Biology; Tumor Immunity; analytical tool; anticancer research; biocomputing; cancer cell; cell type; cohort; community engagement; data integration; data management; draining lymph node; high dimensionality; immune clearance; in situ imaging; insight; interdisciplinary approach; lymph nodes; lymphatic drainage; member; migration; mouse model; multidisciplinary; multimodality; multiscale data; neoplastic cell; next generation; novel; outreach; pre-clinical; prevent; recruit; repository; single cell technology; single-cell RNA sequencing; spatiotemporal; technology platform; tool; transcriptomics; treatment planning; treatment response; tumor; tumor progression

ABSTRACT/SUMMARY – Overall Distant metastasis is the primary cause of cancer-related death. To colonize distant tissues, cancer cells must migrate while evading elimination by the immune system. Evidence suggests that key steps in the induction process of immune tolerance occur early in the metastatic cascade, located at the regional lymph nodes proximal to the primary tumor site. However, the nature of the interactions between malignant, immune and stromal cells remains poorly understood, including those that involve metastatic cells within the lymph nodes. Even though lymph nodes are in fact commonly assessed in cancer patients to determine disease stage and treatment plan, they are understudied in the context of metastatic progression. To fill this scientific knowledge gap, we propose a Research Center to unravel the role of lymph nodes in metastatic progression. We have established that lymph node metastasis constitutes an essential, first step in the metastatic cascade of cancer progression. We have found that such metastases act locally upon the adaptive immune system within the lymph nodes to begin to induce systemic tolerance of the tumor. We will further explore this new paradigm of metastases in two malignancies, head and neck cancer and lung adenocarcinoma, by focusing on the kinetics and spatiotemporal changes at the primary tumor, lymph node and distant sites, associated with the onset and progression of metastasis. We have assembled a multidisciplinary team whose coordinated efforts will involve the application of genomic and single-cell in-situ imaging technologies on preclinical and human samples to explore the evidence and mechanisms of the induction of immunosuppression in the lymph nodes. We propose two Research Projects that focus our scientific theme on lymph node metastasis by analyzing kinetics in a mouse model (Project 1) and spatial temporal changes in samples of lymph nodes and their concurrent primary tumor (Project 2), inter-connected through integrative computational analyses. Both projects will utilize a shared resource core dedicated to the acquisition of patient samples and associated clinical annotation and data management (Biospecimen Core and Data Core). These efforts will yield highly multiplexed, multi-scale datasets which will be analyzed by novel bio-computational methods to reconstruct intracellular and intercellular molecular interaction networks in order to identify, then functionally validate, critical mediators of metastasis. Our ultimate objective is to advance our understanding of the systemic consequences of lymph node metastases and identify new biomarkers and therapeutic approaches. Our Research Center is also dedicated to promoting our early investigators as the next generation thought leaders applying principles of systems biology to the study of metastasis. Our Outreach Core activity will ensure that our Research Center’s scientific and methodological advances in applying the principles of cancer systems biology toward the study of tumor-immune-stromal interactions are fully disseminated in the cancer research and broader communities.

摘要/摘要 - 总体 远处转移是与癌症相关死亡的主要原因。为了定居遥远的时机，癌细胞必须 在免疫系统消除消除的同时迁移。有证据表明归纳的关键步骤 免疫耐受性过程发生在位于区域淋巴结近端的转移性级联反应中 到原发性肿瘤部位。但是，恶性，免疫和基质细胞之间相互作用的性质 仍然知之甚少，包括涉及淋巴结内转移细胞的疾病。虽然 实际上，淋巴结通常在癌症患者中评估以确定疾病阶段和治疗计划， 它们在转移进展的背景下被理解。为了填补这一科学知识差距，我们建议 一个研究中心，旨在阐明淋巴结在转移性进展中的作用。我们已经确定了淋巴 节点转移构成了癌症进展的转移性级联的重要第一步。我们有 发现这种转移在淋巴结内的自适应免疫系统上作用于 诱导肿瘤的全身耐受性。我们将进一步探索两个转移的新范式 通过关注动力学和时空，恶性，头颈癌和肺腺癌 与原发性肿瘤，淋巴结和远处部位的变化，与发作和进展有关 转移。我们组建了一个多学科团队，其协调的努力将涉及申请 临床前和人类样品上的基因组和单细胞原位成像技术，以探索 淋巴结中免疫抑制诱导的证据和机制。我们提出了两个 通过分析鼠标动力学来将我们的科学主题重点放在淋巴结转移上的研究项目 模型（项目1）和淋巴结样品的空间临时变化及其并发原发性肿瘤 （项目2），通过综合计算分析相互联系。这两个项目都将利用共享 用于获取患者样本以及相关临床注释和数据的资源核心 管理（Bispecemen Core和数据核心）。这些努力将产生高度多重的多尺度数据集 这将通过新型生物计算方法进行分析，以重建细胞内和细胞间分子 相互作用网络以识别，然后在功能上验证转移的关键介体。我们的最终 目的是促进我们对淋巴结转移的系统性后果的理解并确定 新的生物标志物和治疗方法。我们的研究中心也致力于提升我们的早期 调查人员作为下一代思想领导者，将系统生物学原理应用于研究 转移。我们的外展核心活动将确保我们的研究中心的科学和方法论 将癌症系统生物学原理用于研究肿瘤 - 免疫性细胞的进展 相互作用在癌症研究和更广泛的社区中完全传播。