Center for 3D Imaging in Cancer Cell Biology

项目摘要--总体 乳腺癌和胰腺癌的死亡率与转移有着内在的联系。在胰腺癌中， 5年存活率只有9%，而在~70%的病理评估中切除的肿瘤，静脉实例 发现了入侵。转移是一个复杂的多步骤过程，涉及癌细胞、局部血管系统和 多个地点周围的微环境。胰腺癌中的静脉侵犯，癌细胞在其中获得 经常侵犯门静脉，是这一过程的早期步骤，并为细胞提供了一条通往肝脏的直接路径 胰腺癌最常见的转移部位。与胰腺癌一样，侵犯超过正常乳腺组织 障碍与乳腺癌的结果密切相关。大多数乳腺肿瘤都可以通过手术切除，因此 死亡率与淋巴管侵犯远处转移的程度密切相关。病毒的检测 乳腺肿瘤的淋巴血管侵犯与不良预后相关，并且不能被当前分子捕获。 分析。癌细胞的空间组织以及肿瘤的细胞和间质成分 血管附近和远处的微环境本质上是三维的、非对称的和 高度异质性。在约翰·霍普金斯3D多尺度癌症成像中心的技术部门，我们 将开发一种通用的3D多尺度成像方法CODA，它将允许我们探测表型 通过多路序列成像显示肿瘤从多厘米到微米尺度的不均一性。尾巴可以很容易地 结合其他成像方式，从3D样本中提取高细胞/分子含量。这些措施包括 免疫细胞化学(CODA+IHC)、免疫荧光(CODA+IF)、成像质谱仪(CODA+IMC) 和空间转录组学/蛋白质组学(CODA+DBiT-seq)。这些建议的CODA扩展版本提供 独一无二的机会来制作新的人体PDAC和乳腺肿瘤的三维多组学图谱 血管。CODA及其集成版本CODA+X将在两个中心的RTB单元中进行测试 人/鼠组织样本和有机物，在乳腺癌和胰腺癌中。这些试验台的结果将 为乳腺癌和胰腺癌的静脉侵袭提供新的机制见解。利用我们广泛的 在数据传播方面的经验，我们将使我们的CODA+X生产的大型数据集和软件 更大的癌症研究社区广泛可用的平台和软件。中心的单位将是 由约翰·霍普金斯大学/耶鲁大学的工程师、科学家和医生共同领导。大量的额外支持将是 由约翰·霍普金斯大学、JH医学院、汇聚研究所、 病理学和怀廷工程学院。

Project Summary - Overall The mortality rates of breast and pancreatic cancers are intrinsically tied to metastasis. In pancreatic cancer, the 5-year survival rate is only 9% and in ~70% pathological evaluations of the resected tumor, instances of venous invasion are found. Metastasis is a complex multi-step process involving cancer cells, local vasculature, and the surrounding microenvironment at multiple sites. Venous invasion in pancreatic cancer, in which cancer cells gain often invade the portal vein, is an early step in this process and provides the cells a direct path to the liver, the most common site of pancreatic cancer metastasis. As in pancreatic cancer, invasion past normal breast tissue barriers is critically tied to breast cancer outcomes. Most breast tumors can be surgically removed, and so mortality is closely tied to the extent of distant metastasis through lymphovascular invasion. The detection of lymphovascular invasion in a breast tumor correlates with poor prognosis and is not captured in current molecular analyses. The spatial organization of cancer cells, and cellular and stromal components of the tumor microenvironment near and far away from blood vessels is intrinsically three-dimensional, non-symmetric, and highly heterogeneous. In the TECH units of the Johns Hopkins Center for 3D Multiscale Cancer Imaging, we will develop a versatile 3D multiscale imaging method, CODA, which will allow us to probe the phenotypic heterogeneity of tumors from the multi-cm to the micron scale via multiplexing serial imaging. CODA can readily incorporate other imaging modalities to extract high cellular/molecular content from 3D samples. These include immunocytochemistry (CODA+IHC), immunofluorescence (CODA+IF), imaging mass cytometry (CODA+IMC) and spatial transcriptomics/proteomics (CODA+DBiT-seq). These proposed expanded versions of CODA offer a unique opportunity to produce new 3D multi-omic maps of human PDAC and breast tumors near and far from blood vessels. CODA and its integrated versions CODA+X will be tested in the RTB units of the Center in both human/mouse tissue samples and organoids, in breast and pancreatic cancer. Results from these test beds will provide novel mechanistic insights into venous invasion in breast and pancreatic cancer. Exploiting our extensive experience in data dissemination, we will make the large datasets and software produced by our CODA+X platforms and software widely available to the larger cancer research community. The units of the Center will be co-led by Johns Hopkins/Yale engineers, scientists and physicians. Substantial additional support will be provided by the Johns Hopkins U., the JH School of Medicine, the Institute for Convergence, the Department of Pathology, and the Whiting School of Engineering.