炎症
胰腺癌
神经炎症
免疫系统
癌症研究
肿瘤微环境
胰腺肿瘤
星形胶质增生
癌症
医学
生物
神经科学
免疫学
内科学
中枢神经系统
作者
Olaya Lara,Pauline Janssen,Marco Mambretti,Laura De Pauw,Gamze Ates,Liselotte Mackens,Jolien De Munck,Jarne Walckiers,Zhaolong Pan,Pauline Beckers,Elisa Espinet,Hideyo Sato,Mark De Ridder,Daniel L. Marks,Kurt Barbé,Joeri L. Aerts,Emmanuel Hermans,Ilse Rooman,Ann Massie
标识
DOI:10.1016/j.bbi.2024.03.001
摘要
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.
科研通智能强力驱动
Strongly Powered by AbleSci AI