Identification of novel paracrine therapeutic targets in peritoneal metastases through integrative proteotranscriptomic analysis of ascites
Year: 2026
Type: article
Abstract: BACKGROUND: Ascites in peritoneal metastases (PM) portends a poor prognosis. However, molecular ligands within ascites and their biological relevance remain unclear. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Source: Molecular Cancer
Authors: Ying Liu, Clara Yieh Lin Chong, Yingrui Wang, Luang Xu, Hui Jun Lim, Qiu Xuan Tan, Josephine Hendrikson, Joey Wee-Shan Tan, Gillian Ng, Wanyu Guo, Youming Wang, Lingling Huang, Weigang Ge, Vinoth Kumar Rethineswaran, Jolynn Zu Lin Ong, Ying En Quek, Andre Jing Yuen Ang, Fionicca Teo, Oris Wanyi Chen, Ananya Rajesh, Yuwei Zhang, Tun Kiat Ko, Bavani Kannan, Boon Yee Lim, Elizabeth Chun Yong Lee, Zexi Guo, Vairavan Lakshmanan, Nicholas Brian Shannon, Nagalakshmi Jegannathan, Craig Ryan Joseph, Zhen Wei Neo, Li Yen Chong, Amanda R. H. Ng, Jia-Ying Joey Lee, Lit-Hsin Loo, Yang Wu, Siyu Zhang, Lanqi Nie, Qiqi Zhang, Lei Zeng, Tony Kiat Hon Lim, Matthew Chau Hsien Ng, Christabel Jing Zhi Lee, Pik Eu Jason Chang, Kevin Kim-Jun Teh, Hiang Keat Tan, Ravichandran Nadarajah, Tze Tein Yong, Junjie Wang, Ieera Madan Aggarwal, Eliza Li Shan Fong, Kenny Zhuoran Wu, Jimmy Bok Yan So, Khay Guan Yeoh, Jolene Si Min Wong, Chin Jin Seo, Mingzhe Cai, Claramae Shulyn Chia, Bin Tean Teh, Iain Beehuat Tan, Joe Yeong, Jason Yongsheng Chan, Tiannan Guo, Chin-Ann Johnny Ong
Institutions: SingHealth, Singapore General Hospital, SingHealth Duke-NUS Academic Medical Centre, Duke-NUS Medical School, National Cancer Centre Singapore, Westlake University, Affiliated Hangzhou First People's Hospital, Westlake University, School of Medicine, National University of Singapore, Agency for Science, Technology and Research, Genome Institute of Singapore, ImmunoQs (Singapore), Bioinformatics Institute, Institute of Molecular and Cell Biology, KK Women's and Children's Hospital, Cancer Science Institute of Singapore, National University Cancer Institute, Singapore, National University Health System, National University Hospital
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,090
Awards: G4404519468, G5228798073
OpenAlex ID: W7212295483