Protein modification partially reverses cancer-related muscle wasting in preclinical study

Cachexia is one of the most severe forms of muscle wasting in humans. It affects up to 80% of cancer patients and is caused by cancer cytokines—pro-inflammatory signaling molecules—that are released by the tumor cells themselves. Depending on the type of cancer, cancer-induced cachexia (CIC) is responsible for 30% to 50% of all cancer-related deaths worldwide and is therefore also referred to as the “final disease.” There is no curative treatment.

To find an effective treatment approach, a research team led by associate professor (Privatdozent, PD) Dr. Arnab Nayak, a scientist at the Institute of Molecular and Cell Physiology at Hanover Medical School (MHH), is investigating the previously unknown processes associated with CIC. With his research group “Chromatin and SUMO Physiology,” he has already demonstrated that cancer cytokines directly interfere with the metabolism of muscle cells and actively reprogram them.

Furthermore, the cytokines ensure that the muscle is unable to release as much calcium, which impairs muscle contraction—that is, the active tightening of the muscle. In his latest study, the molecular biologist outlines the underlying mechanism and presents a possible future approach for a causal treatment. The findings have been published in the journal Cell Death Discovery.

Oxidative stress contributes to muscle wasting

“Research tends to focus on the primary disease, cancer, while the significance of the secondary condition, CIC, is underestimated,” says Nayak. “Yet the significant loss of muscle mass causes a dysregulation of metabolic processes throughout the body and therefore often leads to death even before the actual tumor disease.”

Current treatments tend to focus on alleviating the symptoms. For example, attempts are made to halt muscle wasting through dietary supplements as well as endurance and strength exercises.

The molecular biologist, however, is focusing on the causes of cachexia and is examining the so-called SUMO (small ubiquitin-like modifier) signaling pathway. In this process, known as SUMOylation, the SUMO protein is attached to other proteins to alter their function. SUMO proteins play an important role in the stress response by modifying various enzymes.

“As cachexia is associated with oxidative stress—that is, the imbalance between reactive oxygen species and protective antioxidants—we investigated a possible link between SUMOs and CIC.”

Paradox: Gene silencer activates skeletal muscle genes

In a mouse model and in cell culture, the research team demonstrated that CIC triggered increased SUMOylation of certain proteins in skeletal muscle cells, leading to disrupted calcium homeostasis, disorganization of the sarcomeres—the smallest functional units of the muscle—and impaired muscle contraction. At the same time, the researchers discovered something unexpected: They found that a protein called L3mbtl2 (Lethal(3)malignant brain tumor-like protein 2) activated a large number of muscle-specific genes.

Normally, L3mbtl2 binds to DNA as an epigenetic repressor protein and, acting as a kind of molecular guardian, ensures that the genes at this location cannot be transcribed. “Paradoxically, however, we observed that L3mbtl2 acts as an activator for a large group of muscle-specific genes that regulate sarcomere structure and calcium homeostasis,” says Nayak. Increased SUMOylation of L3mbtl2 in CIC disrupted its binding to DNA, leading to downregulation of these genes and, ultimately, to cachexia.

Mutation in the SUMO conjugation site

As increased SUMOylation of L3mbtl2 was the underlying cause of CIC, the researchers modified the protein’s SUMO conjugation site. This genetic intervention partially reversed the cachexia. The study therefore holds the potential for the development of new therapeutic approaches to alleviate CIC.

“Modulating the SUMOylation process could serve as a possible future approach to improving cachexia—a condition for which there are currently no effective treatments,” Nayak emphasizes.

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Lisa Lock

BA art history, MA material culture. Former museum editor, paramedic, and transplant coordinator. Editing for Science X since 2021.

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Robert Egan

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