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

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

Isotope Applications Research

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

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.

Original language	English
Article number	10751
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-54761-6
State	Published - Dec 2024

Funding

The authors acknowledge the support of Stanford Medicine Catalyst, NIHR01CA250557, R01CA289924 and R01CA253316 to K.W.F. and NIGMS5T32GM007276 to A.J.K. We thank Dr. Jane Chen at the UC Davis Center for Genomic Pathology Lab for mouse tissue IHC and H&E processing. We also thank Peter Chou, Aaron Chiou, and Aya Kondo for guidance using Enable Medicine’s cloud platform. PET/CT/MRI imaging was performed at the Stanford Center for Innovation in In Vivo Imaging (SCi3) and the Canary Center of Stanford University.

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Wang, J., Seo, J. W., Kare, A. J., Schneider, M., Pandrala, M., Tumbale, S. K., Raie, M. N., Engudar, G., Zhang, N., Guo, Y., Zhong, X., Ferreira, S., Wu, B., Attardi, L. D., Pratx, G., Iagaru, A., Brunsing, R. L., Charville, G. W., Park, W. G., & Ferrara, K. W. (2024). Spatial transcriptomic analysis drives PET imaging of tight junction protein expression in pancreatic cancer theranostics. Nature Communications, 15(1), Article 10751. https://doi.org/10.1038/s41467-024-54761-6

@article{23050025c3e842b2af521974d63413b7,

title = "Spatial transcriptomic analysis drives PET imaging of tight junction protein expression in pancreatic cancer theranostics",

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 \textasciitilde{}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 \textasciitilde{}25\% injected activity per cubic centimeter (IA/cc) in metastases and \textasciitilde{}18\% IA/cc in tumors. Our work motivates a data-driven approach to selection of molecular targets.",

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

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year = "2024",

month = dec,

doi = "10.1038/s41467-024-54761-6",

language = "English",

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journal = "Nature Communications",

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Wang, J, Seo, JW, Kare, AJ, Schneider, M, Pandrala, M, Tumbale, SK, Raie, MN, Engudar, G, Zhang, N, Guo, Y, Zhong, X, Ferreira, S, Wu, B, Attardi, LD, Pratx, G, Iagaru, A, Brunsing, RL, Charville, GW, Park, WG & Ferrara, KW 2024, 'Spatial transcriptomic analysis drives PET imaging of tight junction protein expression in pancreatic cancer theranostics', Nature Communications, vol. 15, no. 1, 10751. https://doi.org/10.1038/s41467-024-54761-6

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AU - Seo, Jai Woong

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AU - Schneider, Martin

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AU - Tumbale, Spencer K.

AU - Raie, Marina N.

AU - Engudar, Gokce

AU - Zhang, Nisi

AU - Guo, Yutong

AU - Zhong, Xiaoxu

AU - Ferreira, Sofia

AU - Wu, Bo

AU - Attardi, Laura D.

AU - Pratx, Guillem

AU - Iagaru, Andrei

AU - Brunsing, Ryan L.

AU - Charville, Gregory W.

AU - Park, Walter G.

AU - Ferrara, Katherine W.

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AB - 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.

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

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