Cancer-Associated Weight Loss Is Driven by Hijacked Nerve Signaling and Worsened by Diet

Researchers have identified a signaling pathway through which lung tumors can influence the nervous system and affect eating behaviors, causing a wasting condition that worsens cancer outcomes. 

A combination of cancer-associated genetic mutations and a high-fat diet exacerbated the wasting condition in mouse models, highlighting how diet can modulate tumor behavior and cancer outcomes. 

A genetic link to cachexia 

Cachexia—a complex wasting condition that affects cancer patients and accounts for 20% of all cancer-related deaths—is not well understood and has no effective intervention. 

Cachexia is characterized by the involuntary loss of muscle and fat mass, which renders patients too frail to tolerate treatment, reducing quality of life and increasing mortality. 

Researchers theorize that mediators released from cancer cells and the tumor microenvironment promote cachexia development by inducing metabolic reprogramming or signaling the brain to alter eating behavior. However, whether oncogenic DNA mutations contribute to the production and release of these factors remains unclear. 

In the new study, published in Science, researchers created three genetically engineered mouse models of lung adenocarcinoma, a subtype of non-small cell lung cancer that has a high prevalence of cachexia, to understand how common genetic mutations affect cachexia development. 

Using CRISPR-Cas9, either the Lkb1, Cdkn2a/2b, or P53 locus in mouse models of Kras-driven lung adenocarcinoma was inactivated to model the three major genetic subtypes of this cancer that affect transcription, inflammation, and metabolism. 

Mice with the Lkb1 mutation displayed cachexia symptoms, including weight loss and decreased muscle and fat mass. They also exhibited sickness behaviors, such as reduced water and food intake and decreased activity.  

However, cachexia was not observed in models with mutations to Cdkn2a/2b or P53, suggesting that the Lkb1 mutation plays a key role. 

Dietary interventions can worsen cachexia symptoms 

Dietary interventions are frequently prescribed to restore caloric and nutritional deficiencies and mitigate weight loss in cachexia. However, some patients still lose muscle and fat despite adequate nutrition, and in animal models, dietary interventions have been shown to worsen cachexia symptoms. 

The researchers behind the new study hypothesized that reduced food intake in Lkb1 mutant mice was the major cause of weight loss. Lkb1-deficient mice were given a high-fat diet to investigate whether this would rescue their caloric deficit and weight loss. The other two models were also provided with high-fat diets for comparison. 

Conversely, the high-fat diet triggered dramatic weight loss and reduced survival in the Lkb1 mutant mice, whereas the Cdkn2a/2b and P53 mutant mice gained weight. 

The researchers observed no differences in primary tumor burden between the mouse models, suggesting that loss of Lkb1 in combination with a fat-rich diet exacerbates cachexia and reduces survival through a systemic pathway.

Local signaling molecules cause cachexia 

By comparing fluid from the lungs of Lkb1-deficient mice on a normal diet with those on the high-fat diet, the researchers pinpointed prostaglandin E2 as a potential cause of worsening cachexia. 

Prostaglandin E2 is a signaling molecule that amplifies inflammation and mediates vasodilation and platelet aggregation. Prior research has implicated prostaglandin E2 in driving neural inflammation, muscle protein degradation, and reductions in food intake in cachexia. 

Prostaglandin E2 levels in Lkb1 mutant mice fed a normal diet were also higher than in Cdkn2a/2b and p53-deficient mice fed the same diet. Further, blocking prostaglandin E2 production in Lkb1-deficient mice resulted in improved survival and less weight loss, indicating that prostaglandin E2 plays a cachexia-promoting role. 

“Even though blocking prostaglandin E2 did not shrink the tumors, it made the mice stronger and more able to tolerate the toll lung cancer was taking on their bodies,” said Dr. Thales Y. Papagiannakopoulos, an associate professor at New York University and senior investigator on the new study. 

As prostaglandin E2 levels were elevated only in lung fluid, not in circulating blood, its effects on cachexia are likely to be exerted via the lungs. 

Previously, prostaglandin E2 has been shown to signal to sensory neurons in the lungs, promoting sickness behaviors after influenza infection. The sensory neurons transmit signals from the lungs to the brain via the vagus nerve.

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When Papagiannakopoulos and his team blocked the vagus nerve in animal models, they observed increased food intake, which prevented the common symptoms of cachexia. This finding confirms that cancer-associated prostaglandin E2 signaling promotes cachexia by communicating with the brain via lung neurons and the vagus nerve.  

“Our research shows that tumors can cause cachexia by essentially hacking into the nervous system and altering eating behavior,” said Papagiannakopoulos. “Many groups have studied how molecules circulating throughout the body during chronic disease cause systemic effects in organs like the brain and in muscle. But our work shows that short-range communications, between tumors and nearby cells, called neurons (that are connected to the brain), can cause sickness and cachexia.” 

Prostaglandin E2 is also associated with cachexia in humans 

Papagiannakopoulos and his colleagues also found that prostaglandin E2 levels are elevated in human lung cancer patients who have experienced significant weight loss (>5% over 6 months, or >2% weight loss if their body mass index was less than 20). 

Additionally, in patients with cachexia, transcriptomics analysis of lung fluid cells from the tumor area showed an upregulation of prostaglandin signaling pathways, suggesting that prostaglandin may play a similar role in human cachexia. 

Future work may focus on confirming how prostaglandin E2 contributes to cachexia in humans and identifying therapeutic mechanisms to interfere with its signaling to improve patient outcomes. 

“We hope our research illuminates ways to treat cachexia by blocking harmful signals to the vagus nerve and dietary interventions, so we can help patients be as strong as possible as they fight cancer,” said Papagiannakopoulos. 

Reference: Cross M, Kotschi S, Wu W, et al. A dietary switch promotes sensory neuron–dependent cancer-associated cachexia. Science. 2026. doi: 10.1126/science.adz4196 

This article is a rework of a press release issued by New York University Langone. Material has been edited for length and content.