Endogenous Pancreatic Cancer Cell PD-1 Activates MET and Induces Epithelial-Mesenchymal Transition to Promote Cancer...

Area of Science:

• Oncology
• Molecular Biology
• Cancer Signaling

Background:

• Programmed cell death protein 1 (PD-1) is typically known as an immune checkpoint expressed on immune cells.
• Recent findings indicate PD-1 is endogenously expressed in pancreatic ductal adenocarcinoma (PDAC) cells, suggesting non-immune roles.
• This endogenous PD-1 expression in cancer cells may involve distinct intracellular signaling pathways.

Purpose of the Study:

• To further characterize the role and signaling pathways of endogenously expressed PD-1 in PDAC cells.
• To investigate the functional consequences of PD-1 signaling within PDAC cells.
• To explore the potential of targeting the PD-1 axis in PDAC as a therapeutic strategy.

Main Methods:

• Utilized a phospho-explorer array to identify signaling pathways activated by PD-1 in PDAC cells.
• Investigated the interaction between PD-1 and the MET pathway, including its ligand, hepatocyte growth factor.
• Assessed the effects of combined PD-1 and MET targeting on PDAC cell lines, organoids, and xenografts.

Main Results:

• PD-1 signaling in PDAC cells activates the proto-oncogene MET in a hepatocyte growth factor-dependent manner.
• The PD-1/MET axis promotes PDAC cell growth, migration, invasion, and epithelial-to-mesenchymal transition (EMT).
• Combined targeting of PD-1 and MET induced significant direct tumor cell cytotoxicity and growth inhibition, independent of immune responses.

Conclusions:

• Endogenously expressed PD-1 in PDAC cells regulates MET signaling, driving oncogenic phenotypes.
• The PD-1/MET axis represents a novel, tumor-specific target for directly eliminating PDAC cells.
• Targeting this axis offers a promising therapeutic strategy distinct from traditional immune-based checkpoint inhibition.