Shedding light on melanoma bone metastasis
A new study has revealed the primary mechanism driving bone cell death in bone metastasis caused by melanoma, one of the most aggressive forms of skin cancer. Supported in part by the EU-funded ODE and 4-D nanoSCOPE projects, this research offers a new therapeutic target and paves the way to better manage melanoma-induced bone metastasis. Melanoma often metastasises to bones, resulting in bone loss and an increased risk of fractures and intense pain that significantly affect patients’ quality of life. Bone metastases are also associated with poor survival rates – only 10 % of patients are expected to survive 1 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 of patients with multiple myeloma, a cancer that forms in a type of white blood cell called a plasma cell in the bone marrow. However, it was still unclear precisely how osteocytes contribute to bone metastasis. Given this fact, researchers from ODE and 4-D nanoSCOPE project coordinator Universitätsklinikum Erlangen, Germany, set out to investigate the pathways driving melanoma-induced osteocyte death.
Ferroptosis is the key
In their investigation, the team used both in vivo models and in vitro assays, and combined them with untargeted RNA sequencing approaches. They found that the primary mechanism underlying osteocyte death in melanoma bone metastasis is ferroptosis, an iron-dependent form of cell death characterised by uncontrolled lipid peroxidation. Melanoma cells induce ferroptosis in osteocytes through the upregulation of the protein-coding gene HMOX1. “Since Hmox1 has a pivotal role in heme oxidation and iron metabolism, crucial in ferroptosis, our findings suggest Hmox1 could play a critical role in melanoma metastasis-induced osteocyte ferroptosis,” the authors report in their study. The researchers also uncovered a ferroptosis-related pathway – the HIF1α pathway – that involves excessive autophagy (where the body breaks down and absorbs its own tissue or cells) causing the degradation of ferritin, a protein that stores iron inside cells. Excessive autophagy and ferritin degradation lead to iron overload and lipid peroxidation in the cells – hallmarks of ferroptosis. The HIF1α pathway therefore provides a potential target for modulating HMOX1 expression and influencing autophagy-dependent ferroptosis. Study senior author Aline Bozec, professor in experimental immunotherapy at the Universitätsklinikum Erlangen, explains in a news item posted on ‘AlphaGalileo’: “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 4-D nanoSCOPE (Advancing osteoporosis medicine by observing bone microstructure and remodelling using a four-dimensional nanoscope) project ends in December 2025. ODE (Unknown functions of Osteocyte DEath) ends in May 2026. For more information, please see: ODE project 4-D nanoSCOPE project website
Keywords
ODE, 4-D nanoSCOPE, melanoma, bone, metastasis, cancer, ferroptosis, osteocyte