Research Snapshot: Study explores pathways that fuel muscle wasting in pancreatic cancer

UF Health Cancer Center researchers have identified inflammatory pathways that drive diaphragm muscle wasting in pancreatic cancer, part of a syndrome called cancer cachexia that worsens patients’ quality of life and treatment options.

The researchers explored the histological and transcriptional responses in the mouse diaphragm at multiple timepoints throughout cachexia.

By exploring pathways that fuel the syndrome in mice, the study could contribute to the development of new multimodal treatment approaches for cancer cachexia, which has no FDA-approved treatments and contributes to about 30% of cancer-related deaths. The research, published in the Journal of Cachexia, Sarcopenia and Muscle, was led by UF Health Cancer Center members Andrew Judge, Ph.D., and Sarah Judge, Ph.D.

Cancer cachexia, the unintentional loss of body weight caused by cancer, affects up to 80% of all people with cancer. The loss of body weight is primarily due to the loss of muscle mass, which makes up to 40% of total body weight.

Previous studies by the Judge lab showed similarities between mouse and human respiratory muscles in pancreatic cancer cachexia, including muscle atrophy, inflammation, and replacement of muscle with fibrofatty tissue, which can contribute to muscle dysfunction. Respiratory muscles are needed not only for breathing, but for effective cough production and weakness can lead to respiratory complications.

Whereas most preclinical studies into how skeletal muscle responds to a tumor focus on late-stage cachexia, the new study explored the histological and transcriptional responses in the mouse diaphragm at multiple timepoints throughout cachexia. That allowed the researchers to investigate pathways that might be involved in the development and progression of muscle wasting and changes to muscles caused by the disease.

“One of the most important findings was the increased abundance of white blood cells and activation of inflammatory pathways in muscle before muscle loss,” said Sarah Judge, a research assistant professor in the Department of Physical Therapy in the UF College of Public Health and Health Professions. “Our data support local inflammation as an upstream trigger that may contribute to metabolic reprogramming in muscle and activation of pathways that support the progressive replacement of muscle with fibrofatty tissue.”

Sarah Judge, Ph.D., and Andrew Judge, Ph.D.

Treatment of cancer cachexia requires a multipronged approach targeting various aspects of the syndrome, Judge said. Currently, the most advanced potential treatments in clinical trials are largely focused on increasing appetite in cancer patients.

The new study highlights that inflammation and disruptions to whole body and skeletal muscle metabolism may persist even if nutrition is adequate, Judge said.

“It’s essential that we also find ways to target these other aspects of cachexia that can negatively impact muscle mass and function,” she said.

Now, the Judge lab is focused on identifying and studying pathways and effector molecules that are disrupted before cachexia onset that may contribute to its development and progression. The team is also actively testing novel compounds that improve muscle health to determine whether they can prevent or delay cancer cachexia.

The study’s co-first authors were Daria Neyroud, Ph.D., and Andrew D’Lugos, Ph.D., former postdoctoral research associates in the Judge lab. The study was funded by several National Institutes of Health agencies, including the National Institute of Arthritis, Musculoskeletal and Skin Diseases and the National Cancer Institute.

Read the study in the Journal of Cachexia, Sarcopenia and Muscle.

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