Clinical functional proteomics of intercellular signalling in pancreatic cancer

• 成果类型: Article
• 署名作者: Huang, Peiwu; Gao, Weina; Fu, Changying; Wang, Min; Li, Yunguang; Chu, Bizhu; He, An; Li, Yuan; Deng, Xiaomei; Zhang, Yehan; Kong, Qian; Yuan, Jingxiong; Wang, Hebin; Shi, Yu; Gao, Dong; Qin, Renyi; Hunter, Tony; Tian, Ruijun
• 署名单位: Southern University of Science & Technology; Southern University of Science & Technology; Southern University of Science & Technology; Southern University of Science & Technology; Huazhong University of Science & Technology; Chinese Academy of Sciences; Center for Excellence in Molecular Cell Science, CAS; Salk Institute; Shenzhen Bay Laboratory; Bristol-Myers Squibb
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3261
• DOI: 10.1038/s41586-024-08225-y
• 发表日期: 2025-01-16
• 关键词: protein-tyrosine phosphatases; complement; prediction; enrichment; biology; FAMILY

摘要

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. TMEPro profiles the glycosylated secreted and plasma membrane proteome of 100 human pancreatic tissue samples, defines cell type origins and identifies potential paracrine cross-talk mediated through tyrosine phosphorylation.