Lara, OlayaJanssen, PaulineMambretti, MarcoDe Pauw, LauraAtes, GamzeMackens, LiselotteDe Munck, JolienWalckiers, JarnePan, ZhaolongBeckers, PaulineEspinet, ElisaSato, HideyoDe Ridder, MarkMarks, Daniel L.Barbé, KurtAerts, Joeri L.Hermans, EmmanuelRooman, IlseMassie, Ann2024-07-052024-07-052024-05-011090-2139https://hdl.handle.net/2445/214406xCT (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.12 p.application/pdfengcc by (c) Lara, Olaya et al., 2024http://creativecommons.org/licenses/by/3.0/es/Càncer de pàncreesExpressió gènicaPancreas cancerGene expressioninfo:eu-repo/semantics/article2024-06-20info:eu-repo/semantics/openAccess38447884