New research offers hope for better treatment of bone metastases in people with melanoma.
A new study has revealed the main mechanism that causes osteocyte death in bone metastasis in melanoma, one of the most malignant types of skin cancer. This research, supported in part by the EU-funded projects ODE and 4-D nanoSCOPE, provides a new therapeutic target and paves the way to better treat melanoma-induced bone metastasis. Melanoma often metastasises to the bones, resulting in bone loss, increased risk of fractures and severe pain that significantly reduces the quality of life of those affected. Bone metastasis is also associated with a low survival rate: only 10% of patients survive beyond one year. But what role do osteocytes, the most abundant cells in bone tissue, play in bone metastasis? Higher levels of osteocyte death have been observed in bone lesions in patients with multiple myeloma, a cancer that originates from a type of white blood cell called “plasmacytes” in the bone marrow. However, it was not yet known how osteocytes contribute to bone metastasis. With this in mind, researchers at Universitätsklinikum Erlangen (Germany), the coordinating entity of the ODE and 4-D nanoSCOPE projects, set out to examine the processes that lead to melanoma-induced osteocyte death.
Ferroptosis is the key
In their research, the team used in vivo models, in vitro assays and non-selective RNA sequencing methods. They found that the main mechanism underlying osteocyte death in melanoma bone metastasis is ferroptosis – a type of iron-dependent cell death characterised by uncontrolled lipid peroxidation. Melanoma cells induce ferroptosis in osteocytes through upregulation of the HMOX1 gene, which codes for the protein heme oxygenase-1 (Hmox1). “Since Hmox1 plays a critical role in heme group oxidation and iron metabolism, crucial processes in ferroptosis, our findings suggest that Hmox1 may play a major role in melanoma metastasis-induced osteocyte ferroptosis,” the authors comment in their study. The researchers also discovered a ferroptosis-related pathway, the HIF1α pathway, which involves excessive autophagy (in which the body breaks down and absorbs its own tissues or cells) that leads to the degradation of ferritin, a protein that stores iron in cells. Excessive autophagy and ferritin degradation result in iron overload and lipid peroxidation in cells – two hallmarks of ferroptosis. Therefore, the HIF1α pathway constitutes a potential therapeutic target to modulate HMOX1 expression and influence autophagy-dependent ferroptosis. In a news article published in ‘AlphaGalileo’, Aline Bozec, lead author of the study and professor of Experimental Immunotherapy at Universitätsklinikum Erlangen, comments: “Our research provides a more detailed understanding of the intricate interactions between melanoma cells and the bone microenvironment. By identifying the HIF1α-HMOX1 axis as a key factor in the ferroptosis of osteocytes, we have discovered a promising therapeutic target that could have a major impact on the treatment of bone metastasis”. The 4-D nanoSCOPE (Advancing osteoporosis medicine by observing bone microstructure and remodelling using a four-dimensional nanoscope) project ends in December 2025, while the ODE (Unknown functions of Osteocyte DEath) project ends in May 2026.
More information: European Commission
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