Proteomic and phospho-proteomic longitudinal signatures of human skeletal muscle in lung cancer cachexia

Sorensen, J.; Voldstedlund, C. T.; Battey, E.; Ogueboule, Z.; Irazoki, A.; Modvig, J.; Knos, C.; Hammershoi, A.; Carl, C. S.; Raun, S. H.; Dmytriyeva, O.; Richter, E. A.; Langer, S. W.; Sylow, L.

doi:10.1101/2025.11.26.690647

bioRxiv · 10.1101/2025.11.26.690647

Proteomic and phospho-proteomic longitudinal signatures of human skeletal muscle in lung cancer cachexia

Sorensen, J.·Voldstedlund, C. T.·Battey, E.·Ogueboule, Z.·Irazoki, A.·Modvig, J.·Knos, C.·Hammershoi, A.·Carl, C. S.·Raun, S. H.·Dmytriyeva, O.·Richter, E. A.·Langer, S. W.·Sylow, L.

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Abstract

Weight loss is a potentially deadly hallmark of many cancers, including lung cancer. In particular, the loss of skeletal muscle mass and function impairs survival and lowers quality of life. Despite being a major determinant of prognosis, the molecular drivers of muscle wasting remain ill-defined. Therefore, there is a critical need for human molecular data to support the development of effective therapies for this currently untreatable condition. Here, we utilize cutting-edge proteomics technology to longitudinally map the proteome and phosphoproteome of skeletal muscle from patients with newly diagnosed, advanced-stage non-small cell lung cancer during their treatment. Leveraging deep in vivo clinical phenotyping of activity, body composition, muscle quality, and nutritional risk, we identified 118/174 muscle proteins/phospho-sites associated with cachexia at diagnosis with indications of sexual dimorphism. Treatment altered 278 proteins and 1,155 phospho-sites, of which 137/91 proteins/phospho-sites were associated with muscle wasting. Our findings highlight disrupted calcium, anabolic, and stress signalling, alongside extracellular matrix and mitochondrial alterations, as key molecular features of cachexia in non-small cell lung cancer. These clinically anchored proteomic and phosphoproteomic signatures provide potential targets for future research.

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Sorensen, J., Voldstedlund, C. T., Battey, E., Ogueboule, Z., Irazoki, A., Modvig, J., Knos, C., Hammershoi, A., Carl, C. S., Raun, S. H., Dmytriyeva, O., Richter, E. A., Langer, S. W., Sylow, L.. 2025-11-29. Proteomic and phospho-proteomic longitudinal signatures of human skeletal muscle in lung cancer cachexia. https://doi.org/10.1101/2025.11.26.690647

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