Identification of novel paracrine therapeutic targets in peritoneal metastases through integrative proteotranscriptomic analysis of ascites

Ascites in peritoneal metastases (PM) portends a poor prognosis. However, molecular ligands within ascites and their biological relevance remain unclear. A comprehensive multiomic analysis, including proteomic analysis of 397 malignant cell-free ascites representing 21 histological origins of PM, was performed to decipher pertinent biological themes, identify and validate therapeutically relevant paracrine factors in cell-free ascites, and unravel cell-specific secretion of key paracrine factors. We further developed a nanobody targeting PAI-1 and tested it in vitro, in vivo and ex vivo human explant models. Mass spectrometry analysis identified multiple biological themes including the coagulation cascade. New and previously identified paracrine factors amenable to therapeutic perturbation were also unraveled. Single-cell transcriptomic analysis confirmed secretion of two functionally antagonistic regulators of fibrinolysis (S100A10 and PAI-1) by distinct cell populations in PM ascites, suggesting upregulation of these ligands are due to active secretion by cells rather than homeostatic regulation. We also demonstrated proof of concept of efficacy with minimal toxicity of our nanobody against PAI-1. Collectively, this study explores the biological significance of proteins in malignant cell-free ascites in PM and introduces the therapeutic potential of targeting PAI-1 via a nanobody.

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Publication Details

Journal
Molecular Cancer
Published
2026-09-11
DOI
https://doi.org/10.1186/s12943-026-02787-3
Primary Topic
Intraperitoneal and Appendiceal Malignancies
Type
article
Field-Weighted Citation Impact
0.00

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article

Identification of novel paracrine therapeutic targets in peritoneal metastases through integrative proteotranscriptomic analysis of ascites

Zhuoran Wu, 聂兰启, Fionicca Teo, Clara Y.L. Chong et al.
Molecular Cancer
Intraperitoneal and Appendiceal Malignancies
article

Identification of novel paracrine therapeutic targets in peritoneal metastases through integrative proteotranscriptomic analysis of ascites

Zhuoran Wu, 聂兰启, Fionicca Teo, Clara Y.L. Chong, Iain Beehuat Tan, Bavani Kannan, Tony Kiat Hon Lim, Vairavan Lakshmanan, Christabel Jing Zhi Lee, Tze Tein Yong, Weigang Ge, Elizabeth Chun Yong Lee, Nicholas B. Shannon, Matthew Chau Hsien Ng, Jia-Ying Joey Lee, O. Chen, Ravichandran Nadarajah, Jolene Si Min Wong, Bin Tean Teh, Jason Yongsheng Chan, Jolynn Zu Lin Ong, Lit‐Hsin Loo, Qiu Xuan Tan, Claramae Shulyn Chia, Chin Jin Seo, Josephine Hendrikson, Hiang Keat Tan, Andre Jing Yuen Ang, Joey Wee‐Shan Tan, Boon Yee Lim, Luang Xu, Eliza Li Shan Fong, Gillian Ng, Vinoth Kumar Rethineswaran, Chin‐Ann Johnny Ong, Jimmy Bok Yan So, Hui Jun Lim, Khay Guan Yeoh, Yuwei Zhang, Wanyu Guo, Qiqi Zhang, Mingzhe Cai, Zexi Guo, Li Yen Chong, Tun Kiat Ko, Yang Wu, Nagalakshmi Jegannathan, Ying En Quek, Ieera Madan Aggarwal, Youming Wang, Siyu Zhang, Ananya Rajesh, Craig Ryan Joseph, Lei Zeng, Pik Eu Jason Chang, Amanda R. H. Ng, Ying Liu, Kevin Kim-Jun Teh, Junjie Wang, Joe Yeong, Tiannan Guo, Lingling Huang, Zhen Wei Neo, Yingrui Wang
article en

Abstract

Ascites in peritoneal metastases (PM) portends a poor prognosis. However, molecular ligands within ascites and their biological relevance remain unclear. A comprehensive multiomic analysis, including proteomic analysis of 397 malignant cell-free ascites representing 21 histological origins of PM, was performed to decipher pertinent biological themes, identify and validate therapeutically relevant paracrine factors in cell-free ascites, and unravel cell-specific secretion of key paracrine factors. We further developed a nanobody targeting PAI-1 and tested it in vitro, in vivo and ex vivo human explant models. Mass spectrometry analysis identified multiple biological themes including the coagulation cascade. New and previously identified paracrine factors amenable to therapeutic perturbation were also unraveled. Single-cell transcriptomic analysis confirmed secretion of two functionally antagonistic regulators of fibrinolysis (S100A10 and PAI-1) by distinct cell populations in PM ascites, suggesting upregulation of these ligands are due to active secretion by cells rather than homeostatic regulation. We also demonstrated proof of concept of efficacy with minimal toxicity of our nanobody against PAI-1. Collectively, this study explores the biological significance of proteins in malignant cell-free ascites in PM and introduces the therapeutic potential of targeting PAI-1 via a nanobody.

Molecular Cancer
Agency for Science, Technology and Research (SG), National University of Singapore (SG), Singapore General Hospital (SG), Westlake University (CN), SingHealth Duke-NUS Academic Medical Centre (SG), National University Cancer Institute, Singapore (SG), Advanced Digital Sciences Center (SG), KK Women's and Children's Hospital (SG), Duke-NUS Medical School (SG), National Cancer Centre Singapore (SG), National University Hospital (SG), Bioinformatics Institute (SG), Affiliated Hangzhou First People's Hospital, Westlake University, School of Medicine (CN), National University Health System (SG), Genome Institute of Singapore (SG)
National Medical Research Council
No poverty
Openalex Percentile: Top 8%
Intraperitoneal and Appendiceal Malignancies
DOIOpen Access PDFOpenAlex
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