RANKL/RANK Pathway in Cancer Metastasis and Bone Physiology

The receptor activator of nuclear factor-κB ligand (RANKL) and its receptor RANK constitute a central axis in the regulation of bone remodelling and metastatic spread. In healthy bone, RANKL produced by osteoblasts and stromal cells binds to RANK on osteoclast precursors, driving their differentiation, activation and survival. Osteoprotegerin (OPG) acts as a soluble decoy receptor, sequestering RANKL and restraining osteoclastogenesis. In cancer, dysregulated RANKL/RANK signalling fosters a “vicious cycle” in which tumour cells stimulate osteoclast-mediated bone resorption, releasing growth factors that further support tumour proliferation. Beyond the skeleton, RANKL/RANK influences epithelial-to-mesenchymal transition, immune cell recruitment and stem-like traits in diverse malignancies. Its role in mammary gland physiology underlies hormone-driven epithelial proliferation, while aberrant activation contributes to tumour initiation and progression. Therapeutic targeting of RANKL has thus emerged as a strategy to prevent skeletal-related events in metastatic disease and to modulate tumour-associated immunometabolism.

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RANKL/RANK Pathway in Cancer Metastasis and Bone Physiology publication trend

The graph below shows the total number of articles in rankl/rank pathway in cancer metastasis and bone physiology across all publications each year (not limited to Nature Index journals).

Technical terms

RANKL: A cytokine belonging to the tumour necrosis factor family that binds RANK to activate downstream signalling pathways, promoting osteoclast formation and influencing tumour progression.

RANK: A receptor activator of nuclear factor-κB that, upon binding RANKL, triggers intracellular cascades leading to osteoclastogenesis, immune modulation and metastatic processes.

Osteoprotegerin (OPG): A soluble decoy receptor that binds RANKL, inhibiting its interaction with RANK and thus serving as a negative regulator of bone resorption.

Osteoclast: A specialised bone-resorbing cell derived from the monocyte–macrophage lineage that degrades mineralised matrix in bone remodelling and metastatic bone lesions.

Metastasis: The process through which cancer cells spread from a primary tumour to distant organs, often involving interactions with the bone microenvironment in RANKL/RANK-dependent pathways.

References

1. RANKL/RANK signaling recruits Tregs via the CCL20–CCR6 pathway and promotes stemness and metastasis in colorectal cancer. Cell Death & Disease (2024).
2. Overexpression of TNFSF11 reduces GPX4 levels and increases sensitivity to ferroptosis inducers in lung adenocarcinoma. Journal of Translational Medicine (2024).
3. RANK is a poor prognosis marker and a therapeutic target in ER‐negative postmenopausal breast cancer. EMBO Molecular Medicine (2023).