2. Academic Validation
  3. Bacteria and tumor debris induced pancreatic cancer progression via the NF-κB signaling pathway

Bacteria and tumor debris induced pancreatic cancer progression via the NF-κB signaling pathway

  • Cancer Lett. 2025 Jul 31:632:217964. doi: 10.1016/j.canlet.2025.217964.
Qi Chen 1,  Yonghao Xu 2,  Yisu Wang 3,  Suya Zheng 4,  Tao Yao 5,  Junyu Qiu 6,  Hao Qin 6,  Tingbo Liang 7
Affiliations

Affiliations

  • 1 Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Laboratory of Animal Research Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
  • 2 Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Laboratory of Animal Research Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
  • 3 Zhejiang Hospital, Hangzhou, 310013, China.
  • 4 Department of Surgical Oncology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, 310052, China.
  • 5 Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Academy of Tranditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, China.
  • 6 Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
  • 7 Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China. Electronic address: liangtingbo@zju.edu.cn.
PMID: 40752749 DOI: 10.1016/j.canlet.2025.217964
Abstract

The tumor microenvironment (TME) of metastatic pancreatic ductal adenocarcinoma (PDAC) is characterized by significant cellular and spatial heterogeneity, and long-term hypoxia, leading to micronecrotic regions. PDAC clinical specimens were employed to investigate micronecrosis and we identified that bacteria and lipopolysaccharide (LPS) co-existed in PDAC tissue. Tumor-associated macrophages (TAMs) polarized by these complex components exhibit a distinct pro-inflammatory effect and correlate with drug resistance in pancreatic Cancer. Single-cell data from the GEO database were used to identify differentially enrichment pathways between normal and Cancer tissues. We explored the molecular mechanism of PDAC progression via macrophage-induced inflammation and immune evacuation. The Bacterial components, in conjunction with PDAC debris, induced epithelial-mesenchyme transition in pancreatic Cancer cells by activating nuclear factor kappa B (NF-κB) signaling and increasing programmed cell death ligand 1 (PD-L1) expression in TAMs, thus facilitating tumor progression. We then identified that CBL0137 significantly decreased PD-L1 expression by inhibiting NF-κB signaling and therapeutic efficacy was evaluated through systematic in vivo and in vitro drug experiments, Additionally, CBL0137 could synergize with gemcitabine to enhance its anti-tumor effect. Our results demonstrated the impact of necrosis and inflammation on tumor progression via TAMs and potential therapy strategies, suggesting that CBL0137 may be represented as a promising therapeutic candidate for PDAC.

Keywords

CBL0137; NF-κB; Pancreatic ductal adenocarcinoma; Tumor associated macrophages; Tumor microenvironment.

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