ONCOmmunity

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

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

BioMed Central
2026-09-11; doi: 10.1186/s12943-026-02787-3

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.