Norbert Perrimon's team at Harvard Medical School found that fruit flies with tumors stopped eating protein-rich foods before they lost their appetite entirely — a discovery that could transform how doctors detect the deadly wasting condition known as cancer cachexia.
Cancer cachexia affects the majority of people with advanced cancers, consuming their muscle, fat, and organs until the body essentially consumes itself. It is currently incurable. Detecting it early can slow its progression, but the earliest warning sign doctors had to work with was a general loss of appetite — by which point the disease had often already taken hold.
Now, Perrimon's team has found an earlier signal. Working with fruit flies, researchers discovered that animals with tumors showed a marked decrease in their interest in protein-rich food before they stopped eating altogether. Afroditi Petsakou, who led the work as an HMS research fellow in genetics, observed that the behavioral shift occurred on day four of the study, a full day before the onset of anorexia and two days before organ wasting began.
The team traced the change to two tumor-secreted factors — the inflammatory protein upd3 and the insulin-reducing protein ImpL2 — which together disrupted an appetite regulator in the brain. These factors opened the blood-brain barrier, allowing ImpL2 to prevent neurons from producing the appetite-stimulating neuropeptide NPF. As NPF levels dropped, so did the flies' desire for protein.
The findings are clinically significant because all three components of this molecular chain have human counterparts linked to cancer cachexia: Il-6, IGFBP, and NPY, respectively. Patients with cancer cachexia often report meat aversion and insulin dysregulation — symptoms mirroring what Perrimon's team observed in the flies.
When the researchers interrupted the chain of events, the results were striking. Among flies with an unimpeded cascade, 70 percent died prematurely. Among those where the chain was broken, only 40 percent died.
"By identifying the tumor-derived signals that drive a loss of interest in protein-rich foods, we may be able to detect and intervene in the disease much earlier, when there is still an opportunity to improve outcomes," Perrimon said.
The discovery suggests that a simple shift in food preference — reaching for bread instead of chicken, say, or turning away from eggs — could become a valuable warning sign for clinicians. It also opens a potential avenue for drug development: targeting one or more of the molecular actors in this pathway might help stave off wasting before it becomes irreversible. The work, published in Nature Communications, was part of a Cancer Grand Challenges research initiative dedicated to understanding and treating cachexia.
For the millions of people facing advanced cancer, catching the warning signs earlier could mean the difference between holding onto strength and losing it — one protein craving at a time.