Abstract

xCT (Slc7a11), the specific subunit of the cystine/glutamate antiporter system xc-, 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.

Original languageEnglish
Pages (from-to)275-286
Number of pages12
JournalBrain, Behavior, and Immunity
Volume118
DOIs
Publication statusPublished - May 2024

Bibliographical note

Funding Information:
This work was supported by Kom Op Tegen Kanker (ANI219 to AM and IR), a Strategic research Program of the Vrije Universiteit Brussel (SRP49 to AM), the Scientific Fund Willy Gepts (WFWG – UZ Brussel to PJ), G001619N project from Fund for Scientific Research Flanders (FWO to IR) and the Oncology Research Center (Vrije Universiteit Brussel to PJ). OL, LDP and GA are supported by the FWO (Aspirant fellowship 11C2719N to OL and 11658ON to LPD; postdoctoral fellowship 12B3223N to GA). IR was supported by an FWO Odysseus Fellowship G0F8916N.

Publisher Copyright:
© 2024 The Authors

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