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

Lara, Olaya Janssen, Pauline Mambretti, Marco De Pauw, Laura Ates, Gamze Mackens, Liselotte De Munck, Jolien Walckiers, Jarne Pan, Zhaolong Beckers, Pauline [UCL] Espinet, Elisa Sato, Hideyo De Ridder, Mark Marks, Daniel L Barbé, Kurt Aerts, Joeri L Hermans, Emmanuel [UCL] Rooman, Ilse Massie, Ann et al.[show all]

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