Clinical functional proteomics of intercellular signalling in pancreatic cancer

Peiwu Huang, Weina Gao, Changying Fu, Min Wang, Yunguang Li, Bizhu Chu, An He, Yuan Li, Xiaomei Deng, Yehan Zhang, Qian Kong, Jingxiong Yuan, Hebin Wang, Yu Shi (), Dong Gao (), Renyi Qin (), Tony Hunter and Ruijun Tian ()
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Peiwu Huang: Southern University of Science and Technology
Weina Gao: Southern University of Science and Technology
Changying Fu: Southern University of Science and Technology
Min Wang: Huazhong University of Science and Technology
Yunguang Li: Chinese Academy of Sciences
Bizhu Chu: Southern University of Science and Technology
An He: Southern University of Science and Technology
Yuan Li: Southern University of Science and Technology
Xiaomei Deng: Southern University of Science and Technology
Yehan Zhang: Chinese Academy of Sciences
Qian Kong: Southern University of Science and Technology
Jingxiong Yuan: Huazhong University of Science and Technology
Hebin Wang: Huazhong University of Science and Technology
Yu Shi: Salk Institute for Biological Studies
Dong Gao: Chinese Academy of Sciences
Renyi Qin: Huazhong University of Science and Technology
Tony Hunter: Salk Institute for Biological Studies
Ruijun Tian: Southern University of Science and Technology

Nature, 2025, vol. 637, issue 8046, 726-735

Abstract: Abstract Pancreatic ductal adenocarcinoma (PDAC) has an atypical, highly stromal tumour microenvironment (TME) that profoundly contributes to its poor prognosis1. Here, to better understand the intercellular signalling between cancer and stromal cells directly in PDAC tumours, we developed a multidimensional proteomic strategy called TMEPro. We applied TMEPro to profile the glycosylated secreted and plasma membrane proteome of 100 human pancreatic tissue samples to a great depth, define cell type origins and identify potential paracrine cross-talk, especially that mediated through tyrosine phosphorylation. Temporal dynamics during pancreatic tumour progression were investigated in a genetically engineered PDAC mouse model. Functionally, we revealed reciprocal signalling between stromal cells and cancer cells mediated by the stromal PDGFR–PTPN11–FOS signalling axis. Furthermore, we examined the generic shedding mechanism of plasma membrane proteins in PDAC tumours and revealed that matrix-metalloprotease-mediated shedding of the AXL receptor tyrosine kinase ectodomain provides an additional dimension of intercellular signalling regulation in the PDAC TME. Importantly, the level of shed AXL has a potential correlation with lymph node metastasis, and inhibition of AXL shedding and its kinase activity showed a substantial synergistic effect in inhibiting cancer cell growth. In summary, we provide TMEPro, a generically applicable clinical functional proteomic strategy, and a comprehensive resource for better understanding the PDAC TME and facilitating the discovery of new diagnostic and therapeutic targets.

Date: 2025
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DOI: 10.1038/s41586-024-08225-y

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