RANKL/RANK signaling recruits Tregs via the CCL20-CCR6 pathway and promotes stemness and metastasis in colorectal cancer

  • Cell Death Dis. 2024 Jun 20;15(6):437. doi: 10.1038/s41419-024-06806-3.
Jing Ouyang  1  2 ,  Shuang Hu  3 ,  Qingqing Zhu  1  2 ,  Chenxin Li  1  2 ,  Tingting Kang  1  2 ,  Wenlin Xie  4 ,  Yun Wang  1  2 ,  Yan Li  1  2 ,  Yingsi Lu  1  2 ,  Junhua Qi  5 ,  Ming Xia  1  2 ,  Jinrun Chen  1  2 ,  Yingqian Yang  1  2 ,  Yazhou Sun  1  2  6 ,  Tianshun Gao  1  2  6 ,  Liping Ye  7  8 ,  Qian Liang  9 ,  Yihang Pan  10  11 ,  Chengming Zhu  12  13
Affiliations
  • 1. Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China.
  • 2. Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China.
  • 3. Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
  • 4. Pathological Diagnostic Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China.
  • 5. Department of Clinical Medical Laboratory, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China.
  • 6. Clinical Big Data Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China.
  • 7. Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China. [email protected].
  • 8. Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China. [email protected].
  • 9. Department of Spine Surgery, The First Affiliated Hospital of Shenzhen University, The Shenzhen Second People's Hospital, Shenzhen, China. [email protected].
  • 10. Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China. [email protected].
  • 11. Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China. [email protected].
  • 12. Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China. [email protected].
  • 13. Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China. [email protected].
PMID: 38902257 DOI: 10.1038/s41419-024-06806-3
Abstract

TNF Receptor Superfamily member 11a (TNFRSF11a, RANK) and its ligand TNF Superfamily member 11 (TNFRSF11, RANKL) are overexpressed in many malignancies. However, the clinical importance of RANKL/RANK in colorectal Cancer (CRC) is mainly unknown. We examined CRC samples and found that RANKL/RANK was elevated in CRC tissues compared with nearby normal tissues. A higher RANKL/RANK expression was associated with a worse survival rate. Furthermore, RANKL was mostly produced by regulatory T cells (Tregs), which were able to promote CRC advancement. Overexpression of RANK or addition of RANKL significantly increased the stemness and migration of CRC cells. Furthermore, RANKL/RANK signaling stimulated C-C motif chemokine ligand 20 (CCL20) production by CRC cells, leading to Treg recruitment and boosting tumor stemness and malignant progression. This recruitment process was accomplished by CCL20-CCR6 interaction, demonstrating a connection between CRC cells and immune cells. These findings suggest an important role of RANKL/RANK in CRC progression, offering a potential target for CRC prevention and therapy.

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