Lysosomal Iron Catalyzes Cell Death in Resistant Cancers
A team from French research institutes Centre national de la recherche scientifique (CNRS), Institut Curie, and Institut national de la santé et de la recherche médicale (Inserm) has discovered a new class of molecules capable of inducing the death of cancer cells that are resistant to standard treatments. The study was published in Nature on May 7.
Harnessing Iron's Properties in Cancer Cells
'In certain cancers, such as pancreatic cancer or sarcomas, therapeutic options are relatively limited,' Raphaël Rodriguez, research director at CNRS and co-author of the study, told Medscape's French edition .
Current cancer treatments mainly target primary tumor cells but often fail to eliminate cells with metastatic potential, which are responsible for 70% of cancer-related deaths.
To address this, the team developed a new class of molecules — phospholipid degraders — designed to destroy cancer cell membranes and trigger cell death via ferroptosis.
'We used the properties of iron in cancer cells with metastatic potential. These cells express high levels of the CD44 protein on their surface, which allows them to internalize iron — a resource they need to transform and adapt to standard treatments,' Rodriguez explained.
This transformation, however, also makes them more vulnerable to ferroptosis, a form of cell death catalyzed by iron. Within lysosomes — the small organelles that break down cellular debris and foreign material — iron reacts with hydrogen peroxide, generating oxygen radicals. These radicals damage lysosomal membranes and initiate a chain reaction that spreads throughout the cell, leading to the formation of peroxidized lipids in the membranes of other organelles and ultimately causing cell death.
'We were the first to link cancer, adaptability, and vulnerability to ferroptosis. Cancer cells can adapt, but they don't have a thousand identities. They have two: one that proliferates and one that spreads. Today, we target proliferation. We also need to target dissemination,' said Rodriguez.
Phospholipid Degraders
The researchers developed phospholipid degraders that activate ferroptosis. These molecules contain one segment that targets the cell membrane, enabling penetration and accumulation in lysosomes. A second segment enhances iron reactivity in these compartments of pro-metastatic cancer cells, triggering ferroptosis.
The molecules, named fentomycin-1 (Fento-1), were made fluorescent to confirm their lysosomal localization using fluorescence microscopy.
'Ferroptosis results from the cell's inability to repair membrane damage,' Rodriguez summarized.
Reduction in Tumor Growth
Tested on primary patient-derived cells, tumor organoids, human biopsies, and immunocompetent animal models, these molecules demonstrated greater efficacy than standard treatments.
In preclinical models of metastatic breast cancer, Fento-1 led to a significant reduction in tumor growth. It also showed strong cytotoxic effects in biopsies of pancreatic cancers and angiosarcomas.
'The most interesting results come when we combine these molecules with current treatments. The response is even better,' emphasized Rodriguez.
'We're not saying our treatment will replace existing therapies. We need a combination,' he added. The next steps include toxicity studies, followed by clinical trials. 'Industry and investors should be interested in developing this new therapeutic strategy.'
This work was supported by the Ligue Contre le Cancer (Les équipes labellisées), the European Union's Horizon 2020 research and innovation programme, Fondation pour la Recherche Médicale, Fondation Charles Defforey - Institut de France, Klaus Grohe Foundation, Institut National du Cancer, Région Île-de-France, the French National Research Agency, Fondation Bettencourt Schueller, CNRS, Institut Curie, and Inserm.
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