Necroptosis enhances ‘don’t eat me’ signal and induces macrophage extracellular traps to promote pancreatic cancer liver metastasis

• Published in: Nature communications 2024-07, Vol.15 (1), p.6043-23, Article 6043
• Main Authors: Liao, Cheng-Yu, Li, Ge, Kang, Feng-Ping, Lin, Cai-Feng, Xie, Cheng-Ke, Wu, Yong-Ding, Hu, Jian-Fei, Lin, Hong-Yi, Zhu, Shun-Cang, Huang, Xiao-Xiao, Lai, Jian-Lin, Chen, Li-Qun, Huang, Yi, Li, Qiao-Wei, Huang, Long, Wang, Zu-Wei, Tian, Yi-Feng, Chen, Shi
• Format: Article
• Language: English
• Subjects: 13/106; 13/21; 13/51; 14/19; 14/32; 38/91; 45/91; 631/250/2504/342; 631/67/322; 631/80/82/2344; 692/699/67/1504/1713; 82/1; 82/16; Acrylamides; Adenocarcinoma; Animals; Cancer; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - immunology; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; CD47 Antigen - genetics; CD47 Antigen - metabolism; Cell activation; Cell Line, Tumor; Epithelial-Mesenchymal Transition; Extracellular matrix; Extracellular Traps - metabolism; Female; Gene expression; Gene sequencing; Humanities and Social Sciences; Humans; Immunofluorescence; Immunosurveillance; Immunotherapy; In vivo methods and tests; Intercellular adhesion molecule 1; Intercellular Adhesion Molecule-1 - genetics; Intercellular Adhesion Molecule-1 - metabolism; Kinases; Liver; Liver cancer; Liver Neoplasms - metabolism; Liver Neoplasms - secondary; Macrophages; Macrophages - immunology; Macrophages - metabolism; Male; MAP kinase; Metastases; Metastasis; Mice; multidisciplinary; Necroptosis; Pancreatic cancer; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - immunology; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Protein Kinases - metabolism; Science; Science (multidisciplinary); Signal Transduction; Sulfonamides; Surgery; Traps; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-50450-6

Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer with dismal prognosis due to distant metastasis, even in the early stage. Using RNA sequencing and multiplex immunofluorescence, here we find elevated expression of mixed lineage kinase domain-like pseudo-kinase (MLKL) and enhanced necroptosis pathway in PDAC from early liver metastasis T-stage (T1M1) patients comparing with non-metastatic (T1M0) patients. Mechanistically, MLKL-driven necroptosis recruits macrophages, enhances the tumor CD47 ‘don’t eat me’ signal, and induces macrophage extracellular traps (MET) formation for CXCL8 activation. CXCL8 further initiates epithelial–mesenchymal transition (EMT) and upregulates ICAM-1 expression to promote endothelial adhesion. METs also degrades extracellular matrix, that eventually supports PDAC liver metastasis. Meanwhile, targeting necroptosis and CD47 reduces liver metastasis in vivo. Our study thus reveals that necroptosis facilitates PDAC metastasis by evading immune surveillance, and also suggest that CD47 blockade, combined with MLKL inhibitor GW806742X, may be a promising neoadjuvant immunotherapy for overcoming the T1M1 dilemma and reviving the opportunity for radical surgery. Early-stage liver metastasis of pancreatic ductal adenocarcinoma (PDAC) makes radical surgery not efficacious. Here, the authors show that MLKL-driven necroptosis contributes to PDAC early-stage metastasis by inducing tumour CD47 upregulation and macrophage extracellular traps formation.