2. Academic Validation
  3. GPRC5A/CXCL8/NLRP3-mediated neutrophil extracellular traps drive gemcitabine-nab-paclitaxel resistance in pancreatic adenocarcinoma

GPRC5A/CXCL8/NLRP3-mediated neutrophil extracellular traps drive gemcitabine-nab-paclitaxel resistance in pancreatic adenocarcinoma

  • Cancer Biol Med. 2025 Jul 15;22(7):832-853. doi: 10.20892/j.issn.2095-3941.2025.0040.
Tianyi Zhu # 1,  Qianwen Yang # 1,  Xiaozhe Qian # 2,  Xiuqi Wu 1,  Jianchen Fang 3,  Yuli Lin 4 5,  Yukuan Feng 6,  Jian Gao 7,  Qing Xia 1
Affiliations

Affiliations

  • 1 Department of Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
  • 2 Department of Thoracic Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
  • 3 Department of Pathology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
  • 4 Center for Medical Research and Innovation, Shanghai Pudong Hospital, Shanghai 200030, China.
  • 5 Department of Immunology, Basic Medical School, Shanghai Medical College, Fudan University, Shanghai 200030, China.
  • 6 Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
  • 7 State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.
  • # Contributed equally.
PMID: 40665634 DOI: 10.20892/j.issn.2095-3941.2025.0040
Abstract

Objective: Gemcitabine combined with nab-paclitaxel therapy (GnP) represents first-line chemotherapy for advanced pancreatic ductal adenocarcinoma (PDAC). However, the efficacy of GnP is diminished due to chemotherapeutic resistance induced by the tumor microenvironment (TME), the underlying mechanisms of which remain poorly understood.

Methods: Clinical data from patients with PDAC who underwent GnP therapy were collected and neutrophil infiltration in tumor tissues was assessed. PDAC cell lines and a mouse model of PDAC were utilized to determine the mechanisms underlying GnP resistance and to focus on tumor-associated neutrophils and neutrophil extracellular traps (NETs).

Results: GnP therapy recruited neutrophils to the TME, which resulted in the formation of NETs that contributed to therapeutic resistance in the PDAC murine model. The NET inhibitor, PAD4, enhanced the efficacy of GnP by suppressing tumor growth. Furthermore, GnP significantly upregulated CXCL8 secretion in GnP-resistant MIA PaCa-2 cells, which was mediated by increased expression of GPRC5A in PDAC cells. Screening of classic NET-derived molecules identified cell-free DNA (cfDNA) as a pleiotropic factor that promoted tumor cell proliferation and migration and thereby contributed to chemotherapeutic resistance. In vivo experiments revealed that the combination of GnP with siGPRC5A or DNase was more effective in reducing tumor growth and prolonging survival in PDAC-bearing mice than either treatment alone.

Conclusions: The GPRC5A-CXCL8-NET-cfDNA axis has a critical role in the development of therapeutic resistance to GnP in PDAC. Targeting this axis may represent a promising strategy for overcoming GnP resistance and thereby enhancing the efficacy of chemotherapy in PDAC.

Keywords

GPRC5A; GnP resistance; Pancreatic ductal adenocarcinoma; neutrophil extracellular traps; tumor microenvironment.

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