A breakthrough proteomic study uncovers how melanoma’s mitochondria fuel tumour progression and thwart therapy, opening doors for novel, targeted treatments.
A new study has unveiled a crucial piece of the melanoma puzzle: its mitochondria.
In a groundbreaking proteomic analysis published in Cancer, the journal of the American Cancer Society, researchers have mapped the mitochondrial protein landscape in melanoma, revealing how these cellular powerhouses play a central role in tumour progression and treatment resistance.
The study identifies specific mitochondrial pathways, especially oxidative phosphorylation and mitochondrial translation, as key contributors to melanoma’s aggressiveness and its notorious resistance to therapy.
These findings could reshape therapeutic strategies for advanced melanoma, which remains one of the deadliest forms of skin cancer despite progress in immunotherapy and targeted agents, said senior author Dr Jeovanis Gil, of Lund University in Sweden.
“This discovery identifies melanoma’s excessive reliance on mitochondrial energy as its Achilles’ heel, revealing a therapeutic vulnerability that we can exploit with existing drugs,” he said.
“By pairing mitochondrial blockers with today’s standards of care, we may cut off a major escape route that cancers use to resist therapy and come back.”
Using advanced mass spectrometry and bioinformatics, the researchers mapped the proteins expressed in 151 tumour and normal skin samples.
They identified upregulation of pathways tied to oxidative phosphorylation (OXPHOS) and mitochondrial translation, which they said indicated that melanoma cells were heavily reliant on mitochondrial energy production for survival, proliferation and adaptation to stress, including drug exposure.
Blocking these pathways effectively halted or killed melanoma cells cultured in lab dishes. Two types of drugs accomplished this, including antibiotics that were originally designed to block bacterial protein synthesis machinery, which closely resembles the machinery found in mitochondria.
The other drugs were specialised energy-production inhibitors. Importantly, non-cancerous skin cells remained mostly unaffected, highlighting the safety and specificity of these treatment approaches.
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Dr Gil said the mitochondrial-protein signature his team discovered could be measured in routine biopsy material and could serve as a biomarker to identify patients most likely to benefit from mitochondrial-targeted add-on therapies.
By enabling clinicians to match treatments to each patient’s tumour biology, these findings mark a step forward for precision medicine in melanoma.
Moreover, because mitochondrial rewiring fuels resistance across many cancers, success in melanoma could open the door to similar personalised combination strategies in other hard-to-treat cancers.
“The broader implications of our findings extend beyond melanoma,” the researchers wrote.
“Mitochondrial dysregulation is a hallmark of several cancers, and the ability to repurpose clinically approved antibiotics targeting mitochondrial ribosomes presents an exciting avenue for rapid translational application.
“Furthermore, the metabolic rewiring observed in melanoma, including increased glutamine consumption and altered redox balance, reflects common themes in cancer biology.
“These insights emphasise the need to consider mitochondrial function not just as a biomarker of aggressiveness but as a central node for therapeutic targeting in cancer.”
Patient age at diagnosis was an important correlation in specific mitochondrial proteomic signatures in melanoma, the authors found.
The researchers said older melanoma patients exhibited enhanced expression of mitochondrial proteins associated with metabolic pathways, particularly amino acid and fatty acid metabolism, suggesting increased reliance on mitochondrial energy metabolism in this patient group.
Conversely, younger patients showed enrichment in proteins related to immune response-related pathways.
“These age-dependent metabolic and immune alterations align with previous transcriptomic studies reporting that older melanoma patients possess distinct gene expression profiles characterised by changes in inflammatory and metabolic pathways, which may contribute to poorer melanoma-specific survival and reduced response to immunotherapies compared to younger individuals,” the researchers wrote.
“Thus, age-related differences in mitochondrial metabolism and immune functionality may influence melanoma progression, prognosis and treatment responses, highlighting the importance of incorporating patient age into therapeutic considerations and biomarker discovery.”
Future studies should prioritise clinical trials that integrate mitochondrial inhibitors with existing therapeutic regimens to validate these findings and pave the way for innovative treatments in melanoma and beyond, the researchers concluded.
