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

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

doi:10.1038/s41467-024-54761-6

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

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

Authors

James Wang^#¹, Jai Woong Seo^#¹, Aris J Kare^#^{1

2}, Martin Schneider¹, Mallesh Pandrala¹, Spencer K Tumbale¹, Marina N Raie¹, Gokce Engudar¹, Nisi Zhang¹, Yutong Guo¹, Xiaoxu Zhong³, Sofia Ferreira³, Bo Wu¹, Laura D Attardi^{3

4}, Guillem Pratx³, Andrei Iagaru⁵, Ryan L Brunsing⁶, Gregory W Charville⁷, Walter G Park⁸, Katherine W Ferrara⁹

Affiliations

¹ Molecular Imaging Program at Stanford, Department of Radiology, Stanford University, 300 Pasteur Drive, Stanford, CA, USA.
² Department of Bioengineering, Stanford University, 443 Via Ortega, Stanford, CA, USA.
³ Department of Radiation Oncology, Stanford University, 857 Blake Wilbur Drive, Stanford, CA, USA.
⁴ Department of Genetics, Stanford University, 291 Campus Drive, Stanford, CA, USA.
⁵ Nuclear Medicine and Molecular Imaging Division, Department of Radiology, Stanford University, 300 Pasteur Drive, Stanford, CA, USA.
⁶ Department of Radiology, Stanford University, 300 Pasteur Drive, Stanford, CA, USA.
⁷ Department of Pathology, Stanford University, 300 Pasteur Drive, Stanford, CA, USA.
⁸ Department of Medicine-Gastroenterology & Hepatology, Stanford University, 300 Pasteur Drive, Stanford, CA, USA.
⁹ Molecular Imaging Program at Stanford, Department of Radiology, Stanford University, 300 Pasteur Drive, Stanford, CA, USA. [email protected].

^# Contributed equally.

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.

MeSH terms

Animals
Biomarkers, Tumor / genetics
Biomarkers, Tumor / metabolism
Carcinoma, Pancreatic Ductal* / diagnostic imaging
Carcinoma, Pancreatic Ductal* / genetics
Carcinoma, Pancreatic Ductal* / metabolism
Carcinoma, Pancreatic Ductal* / pathology
Cell Line, Tumor
Claudin-4 / genetics
Claudin-4 / metabolism
Female
Gene Expression Profiling / methods
Gene Expression Regulation, Neoplastic
Humans
Mice
Molecular Imaging / methods
Pancreatic Neoplasms* / diagnostic imaging
Pancreatic Neoplasms* / genetics
Pancreatic Neoplasms* / metabolism
Pancreatic Neoplasms* / pathology
Positron-Emission Tomography* / methods
Proteomics / methods
Tight Junction Proteins / genetics
Tight Junction Proteins / metabolism
Transcriptome

Substances

Claudin-4
Biomarkers, Tumor
Tight Junction Proteins
CLDN4 protein, human

Grants and funding

NIGMS5T32GM007276, NIHR01CA250557, R01CA289924 and R01CA253316/U.S. Department of Health & Human Services | National Institutes of Health (NIH)