A Transgenic Model Reveals the Role of Klotho in Pancreatic Cancer Development and Paves the Way for New Klotho-Based Therapy

• Published in: Cancers
• Main Authors: Arbel Rubinstein, Tammi, Reuveni, Inbal, Hesin, Arkadi, Klein-Goldberg, Anat, Olauson, Hannes, Larsson, Tobias E., Bosch Merino, Assumpció, Chillon Rodriguez, Miguel
• Other Authors: Institut Català de la Salut, Arbel Rubinstein T, Reuveni I, Hesin A Institute of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv 64239, Israel. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel. Klein-Goldberg A Institute of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv 64239, Israel. Olauson H Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, 14186 Stockholm, Sweden. Larsson TE Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, 14186 Stockholm, Sweden. Department of Nephrology, Karolinska University Hospital, 17176 Stockholm, Sweden. Bosch A Klogenix Therapeutics Inc., Boston, MA 02116, USA. Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Spain. Unitat Mixta, Universitat Autònoma de Barcelona, Bellaterra, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. CIBERNED, Instituto de Salud Carlos III, 28029 Madrid, Spain. Chillón M Klogenix Therapeutics Inc., Boston, MA 02116, USA. Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Spain. Unitat Mixta, Universitat Autònoma de Barcelona, Bellaterra, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. ICREA, Institut Catalan Recerca Avançada, 08010 Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus
• Format: Article in Journal/Newspaper
• Language: English
• Published: MDPI 2021
• Subjects: Pàncrees - Càncer - Tractament; Proteïnes supressores de tumors; DISEASES::Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Pancreatic Neoplasms; Other subheadings::Other subheadings::Other subheadings::/drug therapy; CHEMICALS AND DRUGS::Amino Acids; Peptides; and Proteins::Proteins::Neoplasm Proteins::Tumor Suppressor Proteins; ENFERMEDADES::neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias pancreáticas; Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia; COMPUESTOS QUÍMICOS Y DROGAS::aminoácidos; péptidos y proteínas::proteínas::proteínas de neoplasias::proteínas supresoras de tumor; sami
• Online Access: https://hdl.handle.net/11351/7174; https://doi.org/10.3390/cancers13246297

Klotho; Càncer de pàncrees; Supressor del tumor Klotho; Cáncer de páncreas; Supresor de tumor Klotho; Pancreatic cancer; Tumor suppressor Klotho is an anti-aging transmembrane protein, which can be shed and can function as a hormone. Accumulating data indicate that klotho is a tumor suppressor in a wide array of malignancies, and designate the subdomain KL1 as the active region of the protein towards this activity. We aimed to study the role of klotho as a tumor suppressor in pancreatic ductal adenocarcinoma (PDAC). Bioinformatics analyses of The Cancer Genome Atlas (TCGA) datasets revealed a correlation between the survival of PDAC patients, levels of klotho expression, and DNA methylation, and demonstrated a unique hypermethylation pattern of klotho in pancreatic tumors. The in vivo effects of klotho and KL1 were examined using three mouse models. Employing a novel genetic model, combining pancreatic klotho knockdown with a mutation in Kras, the lack of klotho contributed to PDAC generation and decreased mousece survival. In a xenograft model, administration of viral particles carrying sKL, a spliced klotho isoform containing the KL1 domain, inhibited pancreatic tumors. Lastly, treatment with soluble sKL prolonged survival of Pdx1-Cre; KrasG12D/+;Trp53R172H/+ (KPC) mice, a model known to recapitulate human PDAC. In conclusion, this study provides evidence that klotho is a tumor suppressor in PDAC. Furthermore, these data suggest that the levels of klotho expression and DNA methylation could have prognostic value in PDAC patients, and that administration of exogenous sKL may serve as a novel therapeutic strategy to treat PDAC. This project was funded by the The Sami and Tova Sagol Foundation for the Study of Aging, the Margaret Stultz foundation for Pancreatic Cancer Research, the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Ministerio de Ciencia e Innovación ‘Proyectos I+D+I 2019, to M.C., (grant number PID2019-104034RB-I00) and by the TASMC excellence fund. to I.W.