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Updated: Jul 1, 2025

Ultrasound-Guided Orthotopic Implantation of Murine Pancreatic Ductal Adenocarcinoma
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Transmembrane TNF-TNFR2 signaling as a critical immunoregulatory node in pancreatic cancer

Erin M Dickey1, Anna Bianchi1, Haleh Amirian1

  • 1Division of Surgical Oncology, DeWitt Daughtry Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.

Oncoimmunology
|March 14, 2024
PubMed

Insights

Pancreatic cancer

Area of Science:

  • Oncology
  • Immunology
  • Cancer Biology

Background:

  • Pancreatic cancer exhibits significant resistance to conventional therapies.
  • High-risk cancer genomes are linked to complex cellular signaling networks.
  • Therapeutic resistance in pancreatic cancer involves inflammatory processes and immune cell dysfunction.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying therapeutic resistance in pancreatic cancer.
  • To investigate the role of cancer cell-neutrophil interactions in promoting resistance.
  • To identify potential therapeutic targets for sensitizing pancreatic cancer to treatment.

Main Methods:

  • Analysis of cancer cell-neutrophil signaling pathways in pancreatic cancer models.
  • Investigation of transmembrane TNF (tmTNF) and TNFR2 interactions.
  • Assessment of inflammatory polarization in cancer-associated fibroblasts.
  • Evaluation of T-cell dysfunction in the tumor microenvironment.

Main Results:

  • Cancer cell-neutrophil signaling drives neutrophil-derived tmTNF-TNFR2 interactions.
  • These interactions promote inflammatory polarization in cancer-associated fibroblasts.
  • The signaling circuitry also leads to T-cell dysfunction, contributing to resistance.
  • tmTNF-TNFR2 signaling is a key mediator of therapeutic resistance in pancreatic cancer.

Conclusions:

  • Targeting the tmTNF-TNFR2 signaling pathway may overcome therapeutic resistance in pancreatic cancer.
  • Interfering with this circuitry could sensitize pancreatic tumors to chemotherapy and immunotherapy.
  • This finding offers a novel strategy for improving pancreatic cancer treatment outcomes.
Keywords:
ChemotherapyTNFR2immunotherapymyeloid-derived suppressor cellsneutrophilspancreatic cancertumor necrosis factor

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