A new collaborative study from Karolinska Institutet published in Science Advances shows that the levels of mitochondrial DNA (mtDNA) directly influence lung adenocarcinoma (LUAD) progression in mice. LUAD is a common subgroup of human lung cancer that typically contains high levels of mtDNA. The link between high mtDNA levels and tumor progression suggests that mtDNA may provide a new therapeutic target and a biomarker for stratifying patients.
Mitochondrial function has been implicated in cancer for more than 100 years. During the last decades, it has become clear that mitochondrial metabolism is reprogrammed to provide the building blocks cancer cells need to sustain their continuous growth. A large literature shows that mitochondrial DNA levels vary in different cancer types, as exemplified by high mtDNA levels in LUAD. However, few studies have experimentally addressed the role of mtDNA levels in tumor progression.
In a new study published in Science Advances, LUAD was induced by activation of the expression of a mutated Kras oncogene in the lungs of mice with normal or increased mtDNA copy number. The authors found that a higher mtDNA copy number led to an increase in tumor volume. The general rise in mtDNA copy number did not alter the immune cell infiltration in the lung and selective depletion of mtDNA in LUAD tumor cells much reduced tumor growth.
"Taken together, these results argue that mtDNA levels have a tumor cell-intrinsic role in LUAD tumor progression", says Dr. Mara Mennuni at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet and the first author of the study.
The elevated mtDNA levels likely enhance mitochondrial function to provide a functional advantage as the tumor cells grow.
"The results will provide a basis for developing new mitochondrial-targeted cancer therapies and may also be used to stratify patients based on tumor mtDNA levels as a biomarker", says Prof. Nils- Göran Larsson research group leader at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet.
"The next step will be to explore the metabolic processes and cellular pathways that connect elevated mtDNA levels and mitochondrial function to the accelerated growth of lung cancer," says Dr. Mennuni.
Publication
High mitochondrial DNA levels accelerate lung adenocarcinoma progression.
Mennuni M, Wilkie SE, Michon P, Alsina D, Filograna R, Lindberg M, Sanin DE, Rosenberger F, Schaaf A, Larsson E, Pearce EL, Larsson NG
Sci Adv 2024 Nov;10(44):eadp3481
