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

摘要/总结-总体 远处转移是癌症相关死亡的主要原因。为了在远处的组织中定居，癌细胞必须 在逃避免疫系统清除的同时迁移。有证据表明，上岗培训的关键步骤 免疫耐受过程发生在转移级联反应的早期，位于区域淋巴结近端 转移到原发肿瘤部位然而，恶性细胞、免疫细胞和基质细胞之间相互作用的性质 目前还不太清楚，包括那些涉及淋巴结内转移细胞的疾病。即使 淋巴结实际上通常在癌症患者中进行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研究不足。为了填补这一科学知识空白，我们建议 一个研究中心，以解开淋巴结在转移进展中的作用。我们已经建立了淋巴 淋巴结转移构成癌症进展的转移级联中的必要的第一步。我们有 发现这种转移局部作用于淋巴结内的适应性免疫系统，开始 诱导肿瘤的全身耐受性。我们将进一步探讨这种新的转移模式，在两个 恶性肿瘤，头颈癌和肺腺癌，通过关注动力学和时空 原发肿瘤、淋巴结和远处部位的变化，与肿瘤的发生和进展相关， 转移我们已经组建了一个多学科的团队，他们的协调工作将涉及应用 基因组和单细胞原位成像技术在临床前和人体样本，以探索 淋巴结中诱导免疫抑制的证据和机制。我们提出了两 研究项目通过分析小鼠的动力学，将我们的科学主题集中在淋巴结转移上 模型（项目1）和淋巴结及其并发原发性肿瘤样本的时空变化 （项目2），通过综合计算分析相互连接。这两个项目将利用一个共享的 专用于采集患者样本以及相关临床注释和数据的资源核心 管理（生物样本核心和数据核心）。这些努力将产生高度复用的多尺度数据集 将通过新的生物计算方法进行分析，重建细胞内和细胞间的分子 相互作用网络，以确定，然后功能验证，转移的关键介质。我们的最终 目的是提高我们对淋巴结转移的全身后果的理解， 新的生物标志物和治疗方法。我们的研究中心也致力于促进我们的早期 研究人员作为下一代思想领袖，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 肿瘤系统生物学原理在肿瘤免疫间质研究中的应用进展 在癌症研究和更广泛的社区中充分传播相互作用。

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.