Spatial-Genomic Integrative Multi-Species Analysis of Lymph Node Metastasis

淋巴结转移的空间基因组综合多物种分析

• 批准号: 10401199
• 负责人: GARRY P NOLAN
• 金额: $ 48.07万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10401199
• 关键词: Address; Antibodies; Architecture; Biology; Cessation of life; Collaborations; Computer Analysis; Data; Detection; Distant; Distant Metastasis; Freezing; Genomics; Head and Neck Squamous Cell Carcinoma; Heterogeneity; Human; Immune; Immune Tolerance; Immunofluorescence Immunologic; Ligands; Machine Learning; Malignant Neoplasms; Mediator of activation protein; Metastatic Neoplasm to Lymph Nodes; Methods; Mus; Neoplasm Metastasis; Primary Neoplasm; Process; Proteins; RNA; Role; Sampling; Site; Solid Neoplasm; Systems Biology; Tissue Sample; Tissues; Work; analysis pipeline; cancer cell; cell stroma; cell type; chemokine; cohort; computerized tools; cost; cytokine; imaging platform; imaging study; in situ imaging; insight; lymph nodes; melanoma; mouse model; novel; outreach; receptor; single cell analysis; survival outcome; tumor; virtual

PROJECT SUMMARY Metastasis is responsible for the majority of cancer-associated deaths. Dissemination to and colonization of lymph nodes (LNs) precedes metastasis to distant sites in most solid tumors. Our Center in Cancer Systems Biology (CCSB) addresses the central hypothesis that metastasis to distant sites requires systemic immune tolerance induced by early interactions between immune and malignant cells in the metastatic lymph nodes (LN). In Project 1, we have successfully uncovered mechanisms by which metastasis to LNs occurs and the effects of these metastases on the formation of distant metastases, through a murine model of melanoma and have been demonstrating similar phenomena in a murine model of HNSCC. For this cost extension, we will continue our work to evaluate the roles of additional immune subsets in the tolerance process in melanoma and HNSCC, and determine the roles of tumor clonal heterogeneity between primary tumors and LN metastases. In Project 2, we have successfully developed a novel multiplexed immunofluorescence in situ imaging platform, CODEX, to characterize tissue architecture and demonstrated the application of CODEX to fresh frozen and FFPE tissue samples of primary and murine samples of HNSCC and melanoma. For the cost extension, Project 2 aims to continue its work to achieve co-detection of RNA with protein antibodies in CODEX to study the chemokine and cytokine candidates identified in Projects 1 and 3. In Project 3, we developed an integrative single-cell analysis pipelines to study imaging and sequencing data generated in our center. Through this analysis we have identified potentially druggable chemokine ligand-receptor pairs related to lymph node metastasis and validated their functional significance in collaboration with the Project 1 team. Our completed work includes a novel machine learning cell type identification method “CELESTA” to facilitate new insights on spatial biology. For the cost extension, Project 3 aims to continue to apply our computational tools and analysis pipelines to investigate additional immune cell types and stroma cells to identify mediators of tissue architectures facilitating lymph node metastasis on HNSCC tissue samples. We will validate the consistency of the finding on an independent cohort of human HNSCC TMA (Core 3), which is annotated with survival outcomes and collaborate with Project 1 for functional studies. In addition, our Center proposes to continue our efforts in outreach and dissemination through virtual monthly seminars.

项目摘要 转移造成大多数与癌症相关的死亡。传播和殖民 在大多数实体瘤中，淋巴结（LNS）先于转移到远处的转移。我们的癌症系统中心 生物学（CCSB）解决了转移到远处需要全身免疫的中心假设 在转移性淋巴结（LN）中免疫和恶性细胞之间的早期相互作用引起的耐受性。 在项目1中，我们成功地发现了向LN发生转移的机制，以及 这些关于遥远转移形成的转移，通过黑色素瘤的鼠模型，已经是 在HNSCC的鼠模型中表现出类似现象。对于此费用延长，我们将继续我们的 努力评估黑色素瘤和HNSCC的耐受性过程中其他免疫子集的作用，以及 确定原发性肿瘤和LN转移之间肿瘤克隆异质性的作用。在项目2中，我们 成功地开发了一种新型的多重免疫荧光原位成像平台，codex to 表征组织结构并证明了法典在新鲜冷冻和FFPE组织中的应用 HNSCC和黑色素瘤的原发性和鼠样品样本。为了延长成本，项目2的目的是 继续其工作以与法典中的蛋白质抗体共同检测RNA，以研究趋化因子和 在项目1和3中确定的细胞因子候选者。在项目3中，我们开发了一个综合单细胞分析 研究中心生成的成像和测序数据的管道。通过此分析，我们已经确定了 潜在的可吸毒趋化因子配体受体对淋巴结转移的对，并验证了它们 与项目1团队合作的功能意义。我们完成的工作包括一台新颖的机器 学习细胞类型识别方法“ CELESTA”，以促进有关空间生物学的新见解。费用 扩展，项目3旨在继续应用我们的计算工具和分析管道来调查 其他免疫细胞类型和基质细胞，以识别促进淋巴结的组织结构介质 HNSCC组织样品上的转移。我们将验证在独立队列上的发现的一致性 人类HNSCC TMA（核心3）的著作，该元素是通过生存结果注释的，并与项目1合作 功能研究。此外，我们的中心建议继续我们通过宣传和传播努力 虚拟月刊。

项目成果

Profiling Cellular Ecosystems at Single-Cell Resolution and at Scale with EcoTyper.

使用 EcoTyper 以单细胞分辨率和规模分析细胞生态系统。

• DOI: 10.1007/978-1-0716-2986-4_4
• 发表时间: 2023
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Steen,ChloéB;Luca,BogdanA;Alizadeh,AshA;Gentles,AndrewJ;Newman,AaronM
• 通讯作者: Newman,AaronM

Loss of p53-DREAM-mediated repression of cell cycle genes as a driver of lymph node metastasis in head and neck cancer.

• DOI: 10.1186/s13073-023-01236-w
• 发表时间: 2023-11-17
• 期刊: GENOME MEDICINE
• 影响因子: 12.3
• 作者: Brennan, Kevin;Espin-Perez, Almudena;Chang, Serena;Bedi, Nikita;Saumyaa, Saumyaa;Shin, June Ho;Plevritis, Sylvia K.;Gevaert, Olivier;Sunwoo, John B.;Gentles, Andrew J.
• 通讯作者: Gentles, Andrew J.