空间转录组分析推动胰腺癌诊疗中紧密连接蛋白表达的PET成像。

Spatial transcriptomic analysis drives PET imaging of tight junction protein expression in pancreatic cancer theranostics.

作者信息

Wang James, Seo Jai Woong, Kare Aris J, Schneider Martin, Pandrala Mallesh, Tumbale Spencer K, Raie Marina N, Engudar Gokce, Zhang Nisi, Guo Yutong, Zhong Xiaoxu, Ferreira Sofia, Wu Bo, Attardi Laura D, Pratx Guillem, Iagaru Andrei, Brunsing Ryan L, Charville Gregory W, Park Walter G, Ferrara Katherine W

机构信息

Molecular Imaging Program at Stanford, Department of Radiology, Stanford University, 300 Pasteur Drive, Stanford, CA, USA.

Department of Bioengineering, Stanford University, 443 Via Ortega, Stanford, CA, USA.

出版信息

Nat Commun. 2024 Dec 30;15(1):10751. doi: 10.1038/s41467-024-54761-6.

DOI:10.1038/s41467-024-54761-6

PMID:39737976

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11686138/

Abstract

Molecular imaging using positron emission tomography (PET) provides sensitive detection and mapping of molecular targets. While cancer-associated fibroblasts and integrins have been proposed as targets for imaging of pancreatic ductal adenocarcinoma (PDAC), herein, spatial transcriptomics and proteomics of human surgical samples are applied to select PDAC targets. We find that selected cancer cell surface markers are spatially correlated and provide specific cancer localization, whereas the spatial correlation between cancer markers and immune-related or fibroblast markers is low. Claudin-4 expression increases ~16 fold in cancer as compared with normal pancreas, and tight junction localization confers low background for imaging in normal tissue. We develop a peptide-based molecular imaging agent targeted to claudin-4 with accumulation to ~25% injected activity per cubic centimeter (IA/cc) in metastases and ~18% IA/cc in tumors. Our work motivates a data-driven approach to selection of molecular targets.

摘要

使用正电子发射断层扫描（PET）的分子成像可实现对分子靶点的灵敏检测和定位。虽然有人提出将癌症相关成纤维细胞和整合素作为胰腺导管腺癌（PDAC）成像的靶点，但在本文中，我们应用人类手术样本的空间转录组学和蛋白质组学来选择PDAC靶点。我们发现，所选的癌细胞表面标志物在空间上具有相关性，并能提供特定的癌症定位，而癌症标志物与免疫相关或成纤维细胞标志物之间的空间相关性较低。与正常胰腺相比，Claudin-4在癌症中的表达增加了约16倍，紧密连接定位使得在正常组织中成像的背景较低。我们开发了一种靶向Claudin-4的基于肽的分子成像剂，在转移灶中的蓄积量达到每立方厘米约25%注射活性（IA/cc），在肿瘤中的蓄积量达到约18% IA/cc。我们的工作推动了一种数据驱动的分子靶点选择方法。