Lung cancer tumors hijack nervous system to trigger cachexia

Lung cancer tumors hijack nervous system to trigger cachexia

Research led by Thales Papagiannakopoulos, PhD, an incoming Salk professor, has revealed that specific subtypes of lung cancer can control human behavior by tapping into the nervous system. The study, conducted at the New York University (NYU) Grossman School of Medicine, found that these tumors hijack local lung sensory neurons to communicate directly with the brain, exacerbating a wasting syndrome known as cachexia.

Cachexia is a syndrome accompanying chronic illness that results in unwanted loss of muscle and fat, which reduces quality of life and can limit treatment options. According to the Cleveland Clinic, a quarter of cancer deaths can be attributed to this condition. A 2015 German study reported that cachexia affects roughly half of cancer patients and also accompanies cardiovascular disease and Alzheimer's disease, impacting approximately 9 million people globally.

The Mechanism of Muscle Wasting

The wasting process begins with a high demand for energy as the body attempts to fuel an immune response during chronic illness. This often leads to appetite loss, causing the body to consume its own muscle and fat for fuel. While these symptoms were previously attributed to the effects of circulating immune factors, the NYU team used physiologically relevant mouse models—where tumors grew in appropriate locations and human-scale sizes—to discover a neural link.

The researchers identified that one common genetic subset of lung cancer is more prone to promoting cachexia than other subtypes. They discovered that these tumors utilize a signaling molecule called prostaglandin E2 (PGE2) to communicate with the peripheral nervous system. This "lung-brain superhighway" allows tumors to send messages to the brain that trigger cachexia symptoms.

The study found a significant link between diet and the severity of this condition. When researchers provided mice with high-fat, high-calorie chow to counteract weight loss, the condition actually worsened. This is because PGE2 is derived from animal fats, such as omega-6 fatty acids. Conversely, switching to diets containing only omega-3 fatty acids limited the production of PGE2, preventing the tumors from communicating with the brain and stopping the development of cachexia.

Medical interventions that block PGE2 production also proved effective. Cachexia did not develop in mice that were genetically modified to be unable to produce PGE2, nor in smaller trials where mice were given ibuprofen and aspirin.

Future Directions

The discovery of the peripheral nervous system's role in cachexia opens new translational opportunities for cancer care. The research team now aims to pinpoint the exact neurons and brain circuits used by tumors. Stefan Kotschi, MD, a postdoctoral researcher in Papagiannakopoulos' lab, stated the goal is to determine if these same circuits are involved in other cancer-related symptoms, such as memory loss or depression.

By identifying the specific molecules and pathways used in this communication, scientists hope to develop tailored treatments and leverage simple lifestyle changes, such as dietary shifts, to improve long-term patient outcomes.