التفاصيل البيبلوغرافية
| العنوان: |
Endogenous Pancreatic Cancer Cell PD-1 Activates MET and Induces Epithelial-Mesenchymal Transition to Promote Cancer Progression |
| المؤلفون: |
Megan M. Harper, Miranda Lin, Shadi A. Qasem, Reema A. Patel, Michael J. Cavnar, Prakash K. Pandalai, Mei Gao, Joseph Kim |
| المصدر: |
Cancers; Volume 14; Issue 13; Pages: 3051 |
| بيانات النشر: |
Multidisciplinary Digital Publishing Institute |
| سنة النشر: |
2022 |
| المجموعة: |
MDPI Open Access Publishing |
| مصطلحات موضوعية: |
programmed cell death 1 receptor, proto-oncogene protein c-met, epithelial-mesenchymal transition, pancreatic neoplasm, immune checkpoint inhibitors |
| الوصف: |
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. |
| نوع الوثيقة: |
text |
| وصف الملف: |
application/pdf |
| اللغة: |
English |
| Relation: |
Cancer Immunology and Immunotherapy; https://dx.doi.org/10.3390/cancers14133051 |
| DOI: |
10.3390/cancers14133051 |
| الاتاحة: |
https://doi.org/10.3390/cancers14133051 |
| Rights: |
https://creativecommons.org/licenses/by/4.0/ |
| رقم الانضمام: |
edsbas.B5102BA2 |
| قاعدة البيانات: |
BASE |