2. Academic Validation
  3. Clinical functional proteomics of intercellular signalling in pancreatic cancer

Clinical functional proteomics of intercellular signalling in pancreatic cancer

  • Nature. 2025 Jan;637(8046):726-735. doi: 10.1038/s41586-024-08225-y.
Peiwu Huang # 1,  Weina Gao # 1,  Changying Fu # 1,  Min Wang # 2,  Yunguang Li # 3,  Bizhu Chu 1,  An He 1,  Yuan Li 1,  Xiaomei Deng 1,  Yehan Zhang 3,  Qian Kong 1,  Jingxiong Yuan 2,  Hebin Wang 2,  Yu Shi 4 5,  Dong Gao 6 7,  Renyi Qin 8,  Tony Hunter 9,  Ruijun Tian 10
Affiliations

Affiliations

  • 1 State Key Laboratory of Medical Proteomics and Shenzhen Key Laboratory of Functional Proteomics, Department of Chemistry and Research Center for Chemical Biology and Omics Analysis, School of Science and Guangming Advanced Research Institute, Southern University of Science and Technology, Shenzhen, China.
  • 2 Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 3 Key Laboratory of Multi-Cell Systems, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
  • 4 Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA. shiyu.xy@gmail.com.
  • 5 Bristol Myers Squibb, San Diego, CA, USA. shiyu.xy@gmail.com.
  • 6 Key Laboratory of Multi-Cell Systems, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China. dong.gao@sibcb.ac.cn.
  • 7 Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, China. dong.gao@sibcb.ac.cn.
  • 8 Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. ryqin@tjh.tjmu.edu.cn.
  • 9 Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA.
  • 10 State Key Laboratory of Medical Proteomics and Shenzhen Key Laboratory of Functional Proteomics, Department of Chemistry and Research Center for Chemical Biology and Omics Analysis, School of Science and Guangming Advanced Research Institute, Southern University of Science and Technology, Shenzhen, China. tianrj@sustech.edu.cn.
  • # Contributed equally.
PMID: 39537929 DOI: 10.1038/s41586-024-08225-y
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.

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