Metabolome of Pancreatic Juice Delineates Distinct Clinical Profiles of Pancreatic Cancer and Reveals a Link between Glucose Metabolism and PD-1+ Cells
| Autor: | Greta Donisi, Federica Marchesi, Gennaro Nappo, Alessandra Rigamonti, Paola Cappello, Marialuisa Barbagallo, Roberta Avigni, Cristina Ridolfi, Francesca Gavazzi, Alessandro Zerbi, Giovanni Francesco Castino, Paola Allavena, Paolo Monti, Debora Vignali, Daoud Rahal, Panteleimon G. Takis, Giovanni Capretti, Alberto Mantovani, Massimo Roncalli, Nina Cortese, Marco Erreni, Giulia Maggi, Paola Spaggiari, Francesco Novelli |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Cancer Research medicine.medical_treatment Cell Programmed Cell Death 1 Receptor CD8-Positive T-Lymphocytes Transgenic Mice 0302 clinical medicine Pancreatic Juice Leukocytes Medicine Glycolysis Lymphocytes Cells Cultured Glucose Transporter Type 1 Tumor Cultured Aged Animals Biomarkers Tumor Carcinoma Pancreatic Ductal Coculture Techniques Female Humans Leukocytes Mononuclear Lymphocytes Tumor-Infiltrating Mice Transgenic Pancreatic Neoplasms Survival Rate Metabolome medicine.anatomical_structure PFKM Pancreatic Ductal 030220 oncology & carcinogenesis Pancreatectomy Cells Immunology Mononuclear 03 medical and health sciences Pancreatic cancer Tumor-Infiltrating Cancer staging business.industry Carcinoma medicine.disease 030104 developmental biology Pancreatic juice Cancer research business Biomarkers |
| Popis: | Better understanding of pancreatic diseases, including pancreatic ductal adenocarcinoma (PDAC), is an urgent medical need, with little advances in preoperative differential diagnosis, preventing rational selection of therapeutic strategies. The clinical management of pancreatic cancer patients would benefit from the identification of variables distinctively associated with the multiplicity of pancreatic disorders. We investigated, by 1H nuclear magnetic resonance, the metabolomic fingerprint of pancreatic juice (the biofluid that collects pancreatic products) in 40 patients with different pancreatic diseases. Metabolic variables discriminated PDAC from other less aggressive pancreatic diseases and identified metabolic clusters of patients with distinct clinical behaviors. PDAC specimens were overtly glycolytic, with significant accumulation of lactate, which was probed as a disease-specific variable in pancreatic juice from a larger cohort of 106 patients. In human PDAC sections, high expression of the glucose transporter GLUT-1 correlated with tumor grade and a higher density of PD-1+ T cells, suggesting their accumulation in glycolytic tumors. In a preclinical model, PD-1+ CD8 tumor–infiltrating lymphocytes differentially infiltrated PDAC tumors obtained from cell lines with different metabolic consumption, and tumors metabolically rewired by knocking down the phosphofructokinase (Pfkm) gene displayed a decrease in PD-1+ cell infiltration. Collectively, we introduced pancreatic juice as a valuable source of metabolic variables that could contribute to differential diagnosis. The correlation of metabolic markers with immune infiltration suggests that upfront evaluation of the metabolic profile of PDAC patients could foster the introduction of immunotherapeutic approaches for pancreatic cancer. |
| Databáze: | OpenAIRE |
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