Identification of novel paracrine therapeutic targets in peritoneal metastases through integrative proteotranscriptomic analysis of ascites.
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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, Singapore Peritoneal Oncology Study (SPOS) Group and Singapore Gastric Cancer Consortium (SGCC)
Аннотация
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.