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Aggressive skin cancer driven by mitochondrial processes –existing drugs offer promising treatment path

Jeovanis Gil, researcher in clinical chemistry at Lund University. Photo: Tove Smeds
Jeovanis Gil, researcher in clinical chemistry at Lund University, focuses extensively on understanding mitochondrial roles in melanoma and other cancers. Photo: Tove Smeds

A new study led by researchers at Lund University in Sweden, reveals that melanoma, the deadliest form of skin cancer, can in some cases be driven by mitochondrial processes, which can be effectively targeted using existing drugs. In preclinical laboratory experiments with melanoma cell cultures, researchers successfully eliminated cancer cells by using antibiotics and inhibitors of mitochondrial energy production, highlighting a potential therapeutic breakthrough.

Melanoma remains the most aggressive form of skin cancer. Despite major advances in immunotherapy, effective treatments for patients with advanced melanomas are still limited. Now, an international team, led by researchers from Lund University, has identified that certain aggressive melanoma tumours rely heavily on two critical mitochondrial processes. Their findings, published in the scientific journal CANCER, provide new hope for treating melanoma by repurposing drugs already approved for other medical uses.

Mitochondria have long been recognised as the ‘powerhouse’ of the cell due to their crucial role in energy production. However, their involvement in melanoma progression has previously received limited attention. This new study shows that rapidly growing melanoma tumours frequently exhibit overactive mitochondrial protein synthesis and energy production pathways, driving their aggressive growth.

The researchers mapped the mitochondrial signature of melanoma tumours, uncovering a unique biological fingerprint indicating heightened mitochondrial activity.

We identified a mitochondrial signature that is particularly active in the most aggressive melanoma tumours - those in which mitochondria’s own protein synthesis is significantly high, driving tumour growth. This, however, also represents a vulnerability that we can target, says Jeovanis Gil, researcher in clinical chemistry at Lund University and the study’s senior author. 

The research group behind the study focuses extensively on understanding mitochondrial roles in melanoma and other cancers.
The study involved detailed analyses of 151 tissue samples from healthy skin and melanoma tumours, sourced from both living patients and deceased donors. Researchers discovered notably increased mitochondrial activity – particularly energy production (oxidative phosphorylation) and mitochondrial protein synthesis – in the most treatment-resistant melanoma cases, notably in patients with metastatic disease and genetic mutation in the BRAF gene. 

Using existing approved drugs, the team successfully inhibited these tumour-driving mitochondrial processes in laboratory experiments. Treatment of melanoma cells with specific mitochondrial inhibitors and commonly used antibiotics (doxycycline, tigecycline, azithromycin), typically prescribed to disrupt bacterial protein synthesis, resulted in the effective elimination of melanoma cells while sparing healthy skin cells.

The researchers believe that these results strengthen the case for targeting mitochondrial activity as part of future treatments for advanced melanoma. Since the drugs used are already approved for use in humans, the findings open up the possibility of repurposing them for a new use, which could accelerate the process of reaching clinical trials.

“The results apply to laboratory studies in cells and analyses of patient tumours. The findings point to a promising avenue for combination therapy with drugs already approved and available for other indications. But we have not conducted any clinical trials; those will be needed to see if this will also work in humans. So, this is a first step, but it shows that mitochondria are not only part of the cancer process – they may also be the tumour’s Achilles' heel,” says Jeovanis Gil.

Furthermore, the researchers suggest that mitochondrial activity could serve as an early biomarker, helping clinicians predict the risk of melanoma relapse and identify patients who could benefit from such treatment even at an early stage.

“These signatures can be measured in standard biopsy samples, providing a valuable tool for early identification and targeted intervention. We see that the signature is present from the beginning.” 

Short facts about the study: basic research // preclinical, quantitative study // in vitro with cell samples from cancer patients // 

Publication

Mitochondrial proteome landscape unveils key insights into melanoma severity and treatment strategies
DOI: 10.1002/cncr.35897

Funding

The study is a collaboration between researchers in Sweden, Hungary, Brazil, South Korea and the United States and has been funded by the Mrs. Berta Kamprad Foundation and the Crafoord Foundation, among others.

Continued research on mitochondrial vulnerabilities in melanoma will be supported by the Mrs Berta Kamprad Foundation over the next four years.