Compartmentalized role of xCT in supporting pancreatic tumor growth, inflammation and mood disturbance in mice.

Autor: Lara O; Laboratory of Neuro-Aging & Viro-Immunotherapy, Center for Neurosciences (C4N), Vrije Universiteit Brussel (VUB), Brussels 1090, Belgium; Laboratory for Medical and Molecular Oncology, Translational Oncology Research Center (TORC), VUB, Brussels 1090, Belgium., Janssen P; Laboratory of Neuro-Aging & Viro-Immunotherapy, Center for Neurosciences (C4N), Vrije Universiteit Brussel (VUB), Brussels 1090, Belgium; Laboratory for Medical and Molecular Oncology, Translational Oncology Research Center (TORC), VUB, Brussels 1090, Belgium., Mambretti M; Laboratory for Medical and Molecular Oncology, Translational Oncology Research Center (TORC), VUB, Brussels 1090, Belgium., De Pauw L; Laboratory of Neuro-Aging & Viro-Immunotherapy, Center for Neurosciences (C4N), Vrije Universiteit Brussel (VUB), Brussels 1090, Belgium., Ates G; Laboratory of Neuro-Aging & Viro-Immunotherapy, Center for Neurosciences (C4N), Vrije Universiteit Brussel (VUB), Brussels 1090, Belgium., Mackens L; Laboratory of Neuro-Aging & Viro-Immunotherapy, Center for Neurosciences (C4N), Vrije Universiteit Brussel (VUB), Brussels 1090, Belgium., De Munck J; Laboratory of Neuro-Aging & Viro-Immunotherapy, Center for Neurosciences (C4N), Vrije Universiteit Brussel (VUB), Brussels 1090, Belgium., Walckiers J; Laboratory of Neuro-Aging & Viro-Immunotherapy, Center for Neurosciences (C4N), Vrije Universiteit Brussel (VUB), Brussels 1090, Belgium., Pan Z; Laboratory for Medical and Molecular Oncology, Translational Oncology Research Center (TORC), VUB, Brussels 1090, Belgium., Beckers P; Institute of Neuroscience, Université catholique de Louvain, Brussels 1200, Belgium., Espinet E; Pancreatic Cancer Lab, Department of Pathology and Experimental Therapy, School of Medicine, University of Barcelona, L'Hospitalet de Llobregat, Barcelona 08907, Spain; Molecular Mechanisms and Experimental Therapy in Oncology Program, Institut d'Investigació Biomèdica de Bellvitge, L'Hospitalet de Llobregat, Barcelona 08907, Spain., Sato H; Department of Medical Technology, Niigata University, Niigata 950-3198, Japan., De Ridder M; Department of Radiotherapy, UZ Brussels, VUB, Brussels 1090, Belgium., Marks DL; Papé Family Pediatric Research Institute, Oregon Health and Science University, Portland, OR 97239, USA., Barbé K; The Biostatistics and Medical Informatics Department, VUB, Brussels 1090, Belgium., Aerts JL; Laboratory of Neuro-Aging & Viro-Immunotherapy, Center for Neurosciences (C4N), Vrije Universiteit Brussel (VUB), Brussels 1090, Belgium., Hermans E; Institute of Neuroscience, Université catholique de Louvain, Brussels 1200, Belgium., Rooman I; Laboratory for Medical and Molecular Oncology, Translational Oncology Research Center (TORC), VUB, Brussels 1090, Belgium. Electronic address: ilse.rooman@vub.be., Massie A; Laboratory of Neuro-Aging & Viro-Immunotherapy, Center for Neurosciences (C4N), Vrije Universiteit Brussel (VUB), Brussels 1090, Belgium. Electronic address: ann.massie@vub.be.
Jazyk: angličtina
Zdroj: Brain, behavior, and immunity [Brain Behav Immun] 2024 May; Vol. 118, pp. 275-286. Date of Electronic Publication: 2024 Mar 04.
DOI: 10.1016/j.bbi.2024.03.001
Abstrakt: xCT (Slc7a11), the specific subunit of the cystine/glutamate antiporter system x c - , is present in the brain and on immune cells, where it is known to modulate behavior and inflammatory responses. In a variety of cancers -including pancreatic ductal adenocarcinoma (PDAC)-, xCT is upregulated by tumor cells to support their growth and spread. Therefore, we studied the impact of xCT deletion in pancreatic tumor cells (Panc02) and/or the host (xCT -/- mice) on tumor burden, inflammation, cachexia and mood disturbances. Deletion of xCT in the tumor strongly reduced tumor growth. Targeting xCT in the host and not the tumor resulted only in a partial reduction of tumor burden, while it did attenuate tumor-related systemic inflammation and prevented an increase in immunosuppressive regulatory T cells. The latter effect could be replicated by specific xCT deletion in immune cells. xCT deletion in the host or the tumor differentially modulated neuroinflammation. When mice were grafted with xCT-deleted tumor cells, hypothalamic inflammation was reduced and, accordingly, food intake improved. Tumor bearing xCT -/- mice showed a trend of reduced hippocampal neuroinflammation with less anxiety- and depressive-like behavior. Taken together, targeting xCT may have beneficial effects on pancreatic cancer-related comorbidities, beyond reducing tumor burden. The search for novel and specific xCT inhibitors is warranted as they may represent a holistic therapy in pancreatic cancer.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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