Cystine/glutamate antiporter xCT deficiency reduces metastasis without impairing immune system function in breast cancer mouse models

Journal of Experimental & Clinical Cancer Research

Research

Luca Ponzone¹  Enzo Calautti¹  Laura Conti²  Federica Cavallo²  Roberto Ruiu²  Elisabetta Bolli²  Chiara Cossu²  Antonella Iacoviello²  Alekya Rumandla³  Jolanda Magri⁴ 

[1] Department of Molecular Biotechnology and Health Sciences, Laboratory of Epithelial Stem Cell Biology and Signaling, Molecular Biotechnology Center “Guido Tarone”, University of Turin, Via Nizza 52, 10126, Turin, Italy;Department of Molecular Biotechnology and Health Sciences, Laboratory of Oncoimmunology, Molecular Biotechnology Center “Guido Tarone”, University of Turin, Via Nizza 52, 10126, Turin, Italy;Department of Molecular Biotechnology and Health Sciences, Laboratory of Oncoimmunology, Molecular Biotechnology Center “Guido Tarone”, University of Turin, Via Nizza 52, 10126, Turin, Italy;Biocon Bristol Myers Squibb R&D Center, Bommasandra Jigani Link Road, Bommasandra Industrial Area, 560099, Bangalore, Karnataka, India;Department of Molecular Biotechnology and Health Sciences, Laboratory of Oncoimmunology, Molecular Biotechnology Center “Guido Tarone”, University of Turin, Via Nizza 52, 10126, Turin, Italy;Laboratory of Immunotherapy, IIGM - Italian Institute for Genomic Medicine, c/o IRCCS, Candiolo, Italy;Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Italy;

关键词: xCT;    SLC7A11;    Immune system;    Breast cancer;    Metastasis;    Metastatic niche;   

DOI  :  10.1186/s13046-023-02830-x

 received in 2023-06-02, accepted in 2023-09-12,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundThe upregulation of antioxidant mechanisms is a common occurrence in cancer cells, as they strive to maintain balanced redox state and prevent oxidative damage. This includes the upregulation of the cystine/glutamate antiporter xCT, which plays a crucial role in protecting cancer cells from oxidative stress. Consequently, targeting xCT has become an attractive strategy for cancer treatment. However, xCT is also expressed by several types of immune cells where it has a role in proliferation and effector functions. In light of these observations, a comprehensive understanding of the specific role of xCT in the initiation and progression of cancer, as well as its potential impact on the immune system within the tumor microenvironment and the anti-tumor response, require further investigation.MethodsWe generated xCTnull BALB/c mice to investigate the role of xCT in the immune system and xCTnull/Erbb2-transgenic BALB-neuT mice to study the role of xCT in a mammary cancer-prone model. We also used mammary cancer cells derived from BALB-neuT/xCTnull mice and xCTKO 4T1 cells to test the contribution of xCT to malignant properties in vitro and in vivo.ResultsxCT depletion in BALB-neuT/xCTnull mice does not alter autochthonous tumor initiation, but tumor cells isolated from these mice display proliferation and redox balance defects in vitro. Although xCT disruption sensitizes 4T1 cells to oxidative stress, it does not prevent transplantable tumor growth, but reduces cell migration in vitro and lung metastasis in vivo. This is accompanied by an altered immune cell recruitment in the pre-metastatic niche. Finally, systemic depletion of xCT in host mice does not affect transplantable tumor growth and metastasis nor impair the proper mounting of both humoral and cellular immune responses in vivo.ConclusionsxCT is dispensable for proper immune system function, thus supporting the safety of xCT targeting in oncology. Nevertheless, xCT is involved in several processes required for the metastatic seeding of mammary cancer cells, thus broadening the scope of xCT-targeting approaches.

【 授权许可】

CC BY   
© Italian National Cancer Institute ‘Regina Elena’ 2023

【 图 表 】

Fig. 1

Fig. 7

41408_2023_919_Article_IEq13.gif

Fig. 5

Fig. 5