Colorectal tumor-induced orexigenic imbalance lowers protein appetite and drives early organ wasting symptoms

Cancer cachexia (CC) is a deadly syndrome characterized by weight loss and wasting of muscle and adipose tissue ¹ . Early symptoms include behavioral changes such as anorexia (loss of appetite) that precede weight loss and organ wasting ² . Around ∼50-80% of patients with advanced cancer develop CC ³ , generating a pressing need to understand CC progression. Although recent advances have identified distinct metabolic, inflammatory, and neuronal networks associated with CC, the underlying mechanisms initiating early-stage CC remain unclear ¹ . This outstanding question has proven difficult to answer in murine models due to the complexity and onset variability of CC. To address this, we utilized a fly colorectal-tumor model with a defined time-window for organ wasting ⁴ . We discovered that combined increase of conserved factors involved in inflammation (Upd3/Interleukin-6-like) and in reduced insulin signaling (ImpL2/Insulin Growth Factor Binding Protein) cause orexigenic dysfunction prior to organ wasting due to silencing of NPF (Neuropeptide F/ Neuropeptide Y) signaling in the brain. This initiates inadequate protein-specific nutritional choices and anorexia, promoting weight loss. Altogether, we provide evidence for an intricate mechanism that alters protein appetite and drives early organ wasting symptoms.