Tryptophan 2,3-dioxygenase-positive matrix fibroblasts fuel breast cancer lung metastasis via kynurenine-mediated ferroptosis resistance of metastatic cells and T cell dysfunction  

作　　者：Yongcan Liu Shanchun Chen Xueying Wan Rui Wang Haojun Luo Chao Chang Peijin Dai Yubi Gan Yuetong Guo Yixuan Hou Yan Sun Yong Teng Xiaojiang Cui Manran Liu 

机构地区：[1]Key Laboratory of Laboratory Medical Diagnostics,Chinese Ministry of Education,Chongqing Medical University,Chongqing,P.R.China [2]Department of Thyroid and Breast Surgery,The Second Affiliated Hospital of Chongqing Medical University,Chongqing,P.R.China [3]Experimental Teaching Center of Basic Medicine Science,Chongqing Medical University,Chongqing,P.R.China [4]Department of Cell Biology and Medical Genetics,Basic Medical School,Chongqing Medical University,Chongqing,P.R.China [5]Department of Hematology and Medical Oncology,Winship Cancer Institute,Emory University School of Medicine,Atlanta,Georgia,USA [6]Wallace H.Coulter Department of Biomedical Engineering,Georgia Institute of Technology and Emory University,Atlanta,Georgia,USA [7]Department of Surgery,Department of Obstetrics and Gynecology,Samuel Oschin Comprehensive Cancer Institute,Cedars-Sinai Medical Center,Los Angeles,California,USA

出　　处：《Cancer Communications》2024年第11期1261-1286,共26页癌症通讯（英文）

基　　金：supported by National Key Projects of Ministry of Science and Technology of China(MOST 2018YFE0113700);National Natural Science Foundation of China(NSFC82173155,NSFC81874199);the Outstanding Professorship Program of Chongqing Medical University(2019-R10005)to Manran Liu;supported by the Outstanding Postgraduate Fund of Chongqing Medical University(BJRC202021,BJRC202025);the Chongqing Graduate Research and Innovation Project of the Chongqing Education Committee(CYB22218)for Shanchun Chen.

摘　　要：Background:Tumor metastasis is a major threat to cancer patient survival.The organ-specific niche plays a pivotal role in tumor organotropic metas-tasis.Fibroblasts serve as a vital component of the metastatic microenviron-ment,but how heterogeneous metastasis-associated fibroblasts(MAFs)promote organotropic metastasis is poorly characterized.Here,we aimed to decipher the heterogeneity of MAFs and elucidate the distinct roles of these fibroblasts in pulmonary metastasis formation in breast cancer.Methods:Mouse models of breast cancer pulmonary metastasis were estab-lished using an in vivo selection method of repeated injections of metastatic cells purified from the mouse lung.Single-cell RNA-sequencing(scRNA-seq)was employed to investigate the heterogeneity of MAFs.Transgenic mice were used to examine the contribution of tryptophan 2,3-dioxygenase-positive matrix fibroblasts(TDO2^(+)MFs)in lung metastasis.Results:We uncovered 3 subtypes of MAFs in the lung metastatic microenviron-ment,and their transcriptome profiles changed dynamically as lung metastasis evolved.As the predominant subtype,MFs were exclusively marked by platelet-derived growth factor receptor alpha(PDGFRA)and mainly located on the edge of the metastasis,and T cells were enriched around MFs.Notably,high MF sig-natures were significantly associated with poor survival in breast cancer patients.Lung metastases were markedly diminished,and the suppression of T cells was dramatically attenuated in MF-depleted experimental metastatic mouse mod-els.We found that TDO2^(+)MFs controlled pulmonary metastasis by producing kynurenine(KYN),which upregulated ferritin heavy chain 1(FTH1)level in dis-seminated tumor cells(DTCs),enabling DTCs to resist ferroptosis.Moreover,TDO2^(+)MF-secreted chemokines C-C motif chemokine ligand 8(CCL8)and C-C motif chemokine ligand 11(CCL11)recruited T cells.TDO2^(+)MF-derived KYN induced T cell dysfunction.Conditional knockout of Tdo2 in MFs diminished lung metastasis and enhanced immune activation.Conclusions:Our study reveals

关 键 词：Matrix fibroblasts Lung metastasis Tryptophan 2 3-dioxygenase T cell dysfunction Ferropto-sis 

分 类 号：R737.9[医药卫生—肿瘤]