Endogenous Pancreatic Cancer Cell PD-1 Activates MET and Induces Epithelial-Mesenchymal Transition to Promote Cancer Progression
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 exclusive 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. Importantly, the PD-1/MET axis induced epithelial-to-mesenchymal transition (EMT), a well-established 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:14 |
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| Enthalten in: |
Cancers - 14(2022), 13 vom: 21. Juni |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Harper, Megan M [VerfasserIn] |
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| Links: |
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| Themen: |
Epithelial-mesenchymal transition |
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| Anmerkungen: |
Date Revised 12.10.2023 published: Electronic Citation Status PubMed-not-MEDLINE |
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| doi: |
10.3390/cancers14133051 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM343253127 |
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| 520 | |a 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 exclusive 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. Importantly, the PD-1/MET axis induced epithelial-to-mesenchymal transition (EMT), a well-established 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 | ||
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| 700 | 1 | |a Lin, Miranda |e verfasserin |4 aut | |
| 700 | 1 | |a Qasem, Shadi A |e verfasserin |4 aut | |
| 700 | 1 | |a Patel, Reema A |e verfasserin |4 aut | |
| 700 | 1 | |a Cavnar, Michael J |e verfasserin |4 aut | |
| 700 | 1 | |a Pandalai, Prakash K |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Mei |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Joseph |e verfasserin |4 aut | |
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