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

Megan M. Harper, Miranda Lin, Shadi A. Qasem, Reema A. Patel, Michael J. Cavnar, Prakash K. Pandalai, Mei Gao, Joseph Kim

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


We recently demonstrated that immune checkpoint PD-1 was endogenously expressed in pancreatic ductal adenocarcinoma (PDAC) cells. Our data indicated that PD-1 proteins are not ex-clusive to immune cells and have unrecognized signal transduction cascades intrinsic to cancer cells. Building on this paradigm shift, we sought to further characterize PD-1 expression in PDAC. We utilized a phospho-explorer array to identify pathways upregulated by PD-1 signaling. We discovered PD-1-mediated activation of the proto-oncogene MET in PDAC cells, which was dependent on hepatocyte growth factor (MET ligand) and not secondary to direct protein interaction. We then discovered that the PD-1/MET axis in PDAC cells regulated growth, migration, and invasion. Im-portantly, the PD-1/MET axis induced epithelial-to-mesenchymal transition (EMT), a well-estab-lished early oncogenic process in PDAC. We observed that combined targeting of PDAC cell PD-1 and MET resulted in substantial direct tumor cell cytotoxicity and growth inhibition in PDAC cell lines, patient-derived organoids, and patient-derived xenografts independent of cytotoxic immune responses. This is the first report of PDAC-endogenous PD-1 expression regulating MET signaling, which builds upon our growing body of work showing the oncogenic phenotype of PD-1 expression in PDAC cells is distinct from its immunogenic role. These results highlight a paradigm shift that the tumor-specific PD-1 axis is a novel target to effectively kill PDAC cells by antagonizing previously unrecognized PD-1-dependent oncogenic pathways.

Original languageEnglish
Article number3051
Issue number13
StatePublished - Jul 1 2022

Bibliographical note

Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.


  • epithelial-mesenchy-mal transition
  • immune checkpoint inhibitors
  • pancreatic neoplasm
  • programmed cell death 1 receptor
  • proto-oncogene protein c-met

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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