Melanoma metastasis: unveiling the ferroptosis pathway in bone

Melanoma, one of the most aggressive forms of skin cancer, often metastasizes to bones, causing severe bone loss, an increased risk of fractures, and significant pain. Bone metastasis is associated with poor survival rates and a markedly reduced quality of life. Osteocytes, the most abundant cells in bone, are essential for maintaining bone structure and regulating bone remodeling. However, their role in the destruction of bone in melanoma metastasis remains unclear. Understanding the molecular mechanisms driving osteocyte death is crucial to developing effective treatments for melanoma-induced bone metastasis, a condition that poses significant challenges for both researchers and clinicians.

In a recent study (DOI: 10.1038/s41413-024-00384-y) published on January 16, 2025, in Bone Research, researchers from Friedrich-Alexander-University Erlangen-Nürnberg have unveiled ferroptosis as the primary mechanism driving osteocyte death in melanoma bone metastasis. This discovery provides a new therapeutic target and offers hope for improving the management of bone metastases in melanoma patients.

The researchers used both in vivo and in vitro models to investigate the mechanisms underlying osteocyte death. They demonstrated that melanoma cells induce ferroptosis in osteocytes through the upregulation of HMOX1, a gene involved in iron metabolism and heme oxidation. Using an intracardiac melanoma metastasis mouse model and RNA sequencing, the team identified significant alterations in gene expression, particularly in ferroptosis-related pathways. A key discovery was the activation of the HIF1α-HMOX1 axis, which drives excessive autophagy and ferritin degradation, leading to intracellular iron overload and lipid peroxidation, hallmarks of ferroptosis. Notably, inhibiting HMOX1 with the specific inhibitor Znpp significantly reduced osteocyte death and preserved bone integrity, whereas the classical ferroptosis inhibitor, Fer-1, had a lesser effect. The study also raises the possibility of exploring the autophagy-ferroptosis axis in other cancers that metastasize to the bone.

Dr. Aline Bozec, the lead investigator of the study, emphasized the significance of these findings: “Our research offers a deeper understanding of the intricate interactions between melanoma cells and the bone microenvironment. By identifying the HIF1α-HMOX1 axis as a key driver of osteocytes ferroptosis, we have uncovered a promising therapeutic target that could have a profound impact on the treatment of bone metastasis.”

The discovery of ferroptosis as a driver of osteocyte death in melanoma bone metastasis has broad implications for clinical treatment. Targeting the HIF1α-HMOX1 axis could offer a novel approach to reduce osteocyte death and preserve bone integrity, improving the prognosis for melanoma patients with bone metastasis. Moreover, this research strategy need to be extended to other cancers that commonly metastasize to the bone, which in the future could provide a new avenue for treatment. Future research will focus on validating these findings in clinical settings and exploring the development of targeted therapies to address this critical aspect of cancer metastasis.

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References

DOI

10.1038/s41413-024-00384-y

Original Source URL

https://doi.org/10.1038/s41413-024-00384-y

Funding information

This project has received funding from the European Research Council (ERC) under the european union Horizon 2020 research and innovation program (grant agreement ERC co-LS4 ODE (AB) and ERC Synergy Grant 4D Nanoscope(GS)), and Deutsche Forschungsgemeinschaft DFG – Project number 501752319 – TRR369 – DIONE – Project No A02 and B05, FOR 2886 (TP02), CRC1181 (TPA01); DFG funding (450993414) Thunder Imager and the Leibniz Award (GS).

About Bone Research

Bone Research was founded in 2013. As a new English-language periodical, Bone Research focuses on basic and clinical aspects of bone biology, pathophysiology and regeneration, and supports the foremost discoveries resulting from basic investigations and clinical research related to bone. The aim of the Journal is to foster the worldwide dissemination of research in bone-related physiology, pathology, diseases and treatment.