Center for 3D Imaging in Cancer Cell Biology

项目概要-总体 乳腺癌和胰腺癌的死亡率与转移密切相关。在胰腺癌中， 5-年生存率仅为9%，在约70%的切除肿瘤的病理评估中，静脉瘤的情况下， 转移是一个复杂的多步骤过程，涉及癌细胞、局部血管系统和肿瘤细胞。 周围的微环境。胰腺癌的静脉浸润，其中癌细胞获得 通常侵入门静脉，是这个过程的早期步骤，并为细胞提供了一条直接通往肝脏的路径， 最常见的胰腺癌转移部位。就像胰腺癌一样，侵袭过正常的乳腺组织 障碍与乳腺癌的结果密切相关。大多数乳腺肿瘤可以通过手术切除， 死亡率与通过淋巴血管浸润的远处转移的程度密切相关。的检测 乳腺肿瘤中淋巴管浸润与预后不良相关，目前的分子生物学方法没有发现这一点。 分析。癌细胞的空间组织以及肿瘤的细胞和基质成分 靠近和远离血管的微环境本质上是三维的、非对称的， 高度异质性。在约翰霍普金斯三维多尺度癌症成像中心的技术部门，我们 将开发一种多功能的3D多尺度成像方法，CODA，这将使我们能够探测表型 通过多路连续成像，从几厘米到微米尺度的肿瘤异质性。CODA可以很容易地 结合其他成像模式，从3D样本中提取高细胞/分子含量。这些包括 免疫细胞化学（CODA+IHC）、免疫荧光（CODA+IF）、成像质谱细胞术（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 这是一个独特的机会，可以产生人类PDAC和乳腺肿瘤的新的3D多组学图谱， 血管CODA及其集成版本CODA+X将在中心的RTB单元中进行测试， 人/小鼠组织样品和类器官，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浸润提供了新的机制见解。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产生的大型数据集和软件 平台和软件广泛提供给更大的癌症研究社区。该中心的单位将是 由约翰霍普金斯/耶鲁大学的工程师、科学家和医生共同领导。将提供大量额外支助， 由约翰霍普金斯大学提供，JH医学院，融合研究所， 病理学和怀汀工程学院。

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.