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

Cheng-Yu Liao, Ge Li, Feng-Ping Kang, Cai-Feng Lin, Cheng-Ke Xie, Yong-Ding Wu, Jian-Fei Hu, Hong-Yi Lin, Shun-Cang Zhu, Xiao-Xiao Huang, Jian-Lin Lai, Li-Qun Chen, Yi Huang, Qiao-Wei Li, Long Huang, Zu-Wei Wang (), Yi-Feng Tian () and Shi Chen ()
Additional contact information
Cheng-Yu Liao: Shengli Clinical Medical College of Fujian Medical University
Ge Li: Fujian Medical University Union Hospital
Feng-Ping Kang: Shengli Clinical Medical College of Fujian Medical University
Cai-Feng Lin: Shengli Clinical Medical College of Fujian Medical University
Cheng-Ke Xie: Shengli Clinical Medical College of Fujian Medical University
Yong-Ding Wu: Shengli Clinical Medical College of Fujian Medical University
Jian-Fei Hu: Shengli Clinical Medical College of Fujian Medical University
Hong-Yi Lin: Shengli Clinical Medical College of Fujian Medical University
Shun-Cang Zhu: Shengli Clinical Medical College of Fujian Medical University
Xiao-Xiao Huang: Shengli Clinical Medical College of Fujian Medical University
Jian-Lin Lai: Shengli Clinical Medical College of Fujian Medical University
Li-Qun Chen: Fuzhou University
Yi Huang: Shengli Clinical Medical College of Fujian Medical University
Qiao-Wei Li: Shengli Clinical Medical College of Fujian Medical University
Long Huang: Shengli Clinical Medical College of Fujian Medical University
Zu-Wei Wang: Shengli Clinical Medical College of Fujian Medical University
Yi-Feng Tian: Shengli Clinical Medical College of Fujian Medical University
Shi Chen: Shengli Clinical Medical College of Fujian Medical University

Nature Communications, 2024, vol. 15, issue 1, 1-23

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-50450-6

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