2. Academic Validation
  3. Interaction between stromal cells and tumor cells promotes GCB-DLBCL cell survival via the CD40/RANK-KDM6B-NF-κB axis

Interaction between stromal cells and tumor cells promotes GCB-DLBCL cell survival via the CD40/RANK-KDM6B-NF-κB axis

  • Mol Ther. 2025 Jul 2;33(7):3407-3422. doi: 10.1016/j.ymthe.2025.03.025.
Dandan Liu 1,  Haohao Zhang 1,  Yiwang Zhang 2,  Liping Xiao 3,  Jingyao Wang 3,  Shiyan Liao 3,  Hongrui Chen 3,  Huilian Wu 3,  Yiming Hu 1,  Yuhang Jiang 1,  Qi Wang 1,  Cuifeng Li 1,  Pengfei Chen 4,  Yu Zhan 4,  Lingling Li 4,  Ningxia Xie 1,  Deji Ye 1,  Donglin Sun 3,  Yingyong Hou 5,  Yufang Shi 6,  Yongzhong Liu 7,  Jiang Zhu 8,  Wei Li 9,  Chunkui Shao 10,  Xiaoren Zhang 11
Affiliations

Affiliations

  • 1 Affiliated Guangzhou Women and Children's Medical Center, The Second Affiliated Hospital, Affiliated Cancer Hospital/Institute and GMU-GIBH Joint School of Life Sciences of Guangzhou Medical University, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangdong Provincial Key Laboratory of Allergy and Clinical Immunology, State Key Laboratory of Respiratory Disease, Guangzhou 510182, China; CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
  • 2 Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510632, China.
  • 3 Affiliated Guangzhou Women and Children's Medical Center, The Second Affiliated Hospital, Affiliated Cancer Hospital/Institute and GMU-GIBH Joint School of Life Sciences of Guangzhou Medical University, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangdong Provincial Key Laboratory of Allergy and Clinical Immunology, State Key Laboratory of Respiratory Disease, Guangzhou 510182, China.
  • 4 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
  • 5 Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
  • 6 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; Soochow University Institutes for Translational Medicine, Soochow 215123, China.
  • 7 State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200025, China.
  • 8 Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Collaborative Innovation Center of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China.
  • 9 Affiliated Guangzhou Women and Children's Medical Center, The Second Affiliated Hospital, Affiliated Cancer Hospital/Institute and GMU-GIBH Joint School of Life Sciences of Guangzhou Medical University, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangdong Provincial Key Laboratory of Allergy and Clinical Immunology, State Key Laboratory of Respiratory Disease, Guangzhou 510182, China. Electronic address: leways@lzu.edu.cn.
  • 10 Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510632, China. Electronic address: shaochk@mail.sysu.edu.cn.
  • 11 Affiliated Guangzhou Women and Children's Medical Center, The Second Affiliated Hospital, Affiliated Cancer Hospital/Institute and GMU-GIBH Joint School of Life Sciences of Guangzhou Medical University, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangdong Provincial Key Laboratory of Allergy and Clinical Immunology, State Key Laboratory of Respiratory Disease, Guangzhou 510182, China; CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: xrzhang@gzhmu.edu.cn.
PMID: 40119515 DOI: 10.1016/j.ymthe.2025.03.025
Abstract

The stromal cells as the main component of the tumor microenvironment in germinal center B cell-like diffuse large B cell lymphoma (GCB-DLBCL) probably is accountable for therapy resistance and relapse. To investigate the interaction between tumor cells and stromal cells, we established GCB-DLBCL patient-derived xenograft models to isolate primary tumor cells and coculture them with stromal cells. Additionally, we presented GCB-DLBCL cases with histopathologic confirmation and analyzed the online databases to explore the underlying mechanisms. We demonstrated that CD40 ligand (CD40L) expressed on stromal cells activated the CD40 pathway in GCB-DLBCL tumor cells, protecting tumor cells from Apoptosis and up-regulating RANK ligand (RANKL). The RANKL expressed on tumor cells enhanced the expression of CD40L and BAFF in stromal cells, which in turn promoted tumor cells survival through activating NF-κB signaling. Significantly, the activation of CD40 pathway up-regulated KDM6B, a lysine-specific demethylase, and KDM6B further enhanced the transcription activity of NF-κB signaling, which has not been reported in B cells. Here, we provided compelling evidence that the interaction between stromal cells and tumor cells functions as a bona fide anti-apoptotic factor in GCB-DLBCL. This interaction mainly involves the CD40/RANK-KDM6B-NF-κB axis, which represents a promising therapeutic target for GCB-DLBCL.

Keywords

CD40 pathway; GCB-DLBCL; KDM6B; NF-κB signaling; PDX model; RANK pathway; antiapoptosis; stromal cells; stromal-tumor interaction; tumor microenvironment.

Figures
Products