RTB 1

实时TB 1

• 批准号: 10886852
• 负责人: Laura DeLong Wood
• 金额: $ 8.19万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10886852
• 关键词: 3-Dimensional; Antibodies; Area; Automobile Driving; Beds; Biological; Cells; Cellular Assay; Clinical; Collaborations; Complex; Cytometry; Development; Dimensions; Disease; Distant Metastasis; Epithelium; Event; Fibroblasts; Foundations; Frequencies; Gene Expression Profiling; Goals; Human; Image; Imaging technology; Immune; Inflammatory; Invaded; Label; Liver; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Maps; Mesenchymal; Molecular; Molecular Analysis; Morphology; Neoplasm Metastasis; Pancreas; Pancreatic Ductal Adenocarcinoma; Performance; Population; Primary Neoplasm; Process; Prognosis; Proteomics; Research; Resolution; Sampling; Stromal Cells; Structure; Techniques; Testing; Tissue Model; Tissue Sample; Tissues; Validation; Veins; Venous; Work; cancer cell; cancer imaging; cell type; deep learning; dimensional analysis; high dimensionality; human tissue; imaging platform; improved; insight; mouse model; multi-scale modeling; multiple omics; new therapeutic target; novel; novel strategies; pancreatic cancer model; pancreatic ductal adenocarcinoma cell; pancreatic neoplasm; pancreatic tumorigenesis; prevent; programs; reconstruction; synergism; technology development; tool; transcriptome; transcriptomics; tumor microenvironment

Project Summary Pancreatic cancer is a deadly disease with a dismal prognosis and a high frequency of distant metastasis. One likely reason for the frequent metastases in pancreatic cancer is the ability of malignant cells in the primary tumor to invade veins, providing direct access to the liver. While this intravasation is a key first step in metastasis, little is known about the molecular and cellular alterations that underlie this process. Foci of cancer cell intravasation are small and complex, requiring high-resolution three-dimensional (3D) approaches to study them. In this Research Test Bed of our Center for 3D Multiscale Cancer Imaging, we will comprehensively characterize the morphological, cellular, and molecular alterations of foci of intravasation in 3D in human pancreatic cancer samples. In collaboration with Technology Development Unit 1, we will employ our novel deep learning 3D reconstruction approach CODA to serially sectioned pancreatic cancer samples with venous invasion to quantify morphological and cellular features of intravasation. We will also perform multi-dimensional immune profiling of these intravasation foci in 3D using imaging mass cytometry, which can label with 40 antibodies on each tissue section. These analyses will allow us to compare the tumor microenvironment in foci of intravasation to that in other areas of cancer and in uninvolved veins. In collaboration with Technology Development Unit 2, we will analyze the gene expression changes in these intravasation foci by applying a newly developed spatial transcriptomics/proteomics approach (DBit-Seq) to pancreatic cancer samples previously reconstructed by CODA. This approach will provide the first 3D multi-scale models of venous invasion in human pancreatic cancer, providing unprecedented morphological, cellular, and molecular detail of the process of intravasation and initiation of metastasis. In addition, our Research Test Bed will provide a critical opportunity to implement, validate, and iteratively improve the novel approaches from the two Technology Development Centers. We will work closely with these Technology Development Centers in order to evaluate the performance of CODA and DBit-Seq in our human pancreatic tissue samples, allowing validation of the cell type identification and molecular alterations by complementary techniques. The studies in our Research Test Bed will promote significant improvement of the CODA and DBit-Seq imaging platforms while also providing important biological insights into the initiation of metastasis in pancreatic cancer.

项目摘要 胰腺癌是一种预后差、易发生远处转移的致命疾病。一 胰腺癌频繁转移的可能原因是原发肿瘤中恶性细胞的能力 侵入静脉直接进入肝脏虽然这种内渗是转移的关键第一步， 是已知的分子和细胞的变化，这一过程的基础。癌细胞浸润灶 小而复杂，需要高分辨率的三维（3D）方法来研究它们。在这 我们的3D多尺度癌症成像中心的研究测试床，我们将全面表征 人胰腺癌血管内浸润灶的三维形态、细胞和分子改变 样品在与技术开发单位1的合作中，我们将采用我们新颖的深度学习3D技术， 重建方法CODA连续切片的胰腺癌样本与静脉浸润，以量化 内渗的形态学和细胞学特征。我们还将进行多维免疫分析， 使用成像质量细胞术在3D中观察这些血管内病灶，每个组织上可以标记40种抗体 科.这些分析将使我们能够比较肿瘤微环境的病灶内渗， 其他癌症区域和未受累静脉。我们会与技术发展组（二）合作， 应用新开发的空间分析技术分析这些血管内渗灶的基因表达变化 转录组学/蛋白质组学方法（DBit-Seq）对先前通过 结尾这种方法将提供人类胰腺癌静脉浸润的第一个3D多尺度模型， 提供了前所未有的形态学、细胞和分子细节的内渗过程， 转移的开始。此外，我们的研究试验台将提供一个实施的关键机会， 验证和迭代改进来自两个技术开发中心的新方法。我们将 与这些技术开发中心密切合作，以评估CODA的性能， 在我们的人类胰腺组织样本中使用DBit-Seq，可以验证细胞类型鉴定和分子生物学特性。 通过补充技术进行改造。在我们的研究试验床的研究将促进显着 CODA和DBit-Seq成像平台的改进，同时还提供了重要的生物学见解， 胰腺癌转移的起始。