Cancer Hijacks Muscle's Internal Clock to Drive Deadly Wasting via FOXP1

Cancer cachexia—the involuntary, progressive loss of skeletal muscle mass—affects most advanced cancer patients and significantly worsens outcomes, reducing treatment tolerance and increasing mortality. While molecular drivers of muscle wasting have been studied, the role of circadian clock disruption in this process was largely unexplored. This study investigates how cancer-induced upregulation of the transcription factor FOXP1 rewires the skeletal muscle circadian transcriptome to promote wasting.

Using chromatin immunoprecipitation sequencing (ChIP-seq) in a KPC orthotopic pancreatic cancer mouse model, the researchers mapped FOXP1 DNA-binding sites across the skeletal muscle genome under cancer-free and tumor-bearing conditions. They identified over 5,600 FOXP1-binding sites in cancer muscle, with notable enrichment at promoters of core circadian clock genes including Bmal1, Per1, Cry1, and Cry2. FOXP1-bound genes also included key players in autophagy, ubiquitin-proteasome proteolysis, insulin signaling, and lipid metabolism pathways—many of which are newly bound only under cancer conditions.

To assess functional consequences, mice with and without skeletal-muscle-specific FoxP1 knockout (FoxP1SkmKO) were studied over 24-hour circadian time courses via RNA-seq. In wild-type cancer mice, 991 of 1,337 normally rhythmic genes lost their circadian oscillation, particularly those governing glucose transport, fatty acid oxidation, and carbohydrate metabolism. Simultaneously, 809 non-rhythmic genes gained rhythmicity in cancer, enriched for macrophage activation, neutrophil activation, proteasomal degradation, and autophagy—classic cachexia pathways. Strikingly, 90% of this cancer-induced gain of rhythmicity required FoxP1, and 130 of these genes were direct FOXP1 ChIP-seq targets.

At the core clock level, cancer biased expression toward the negative arm (elevated Per1, Cry1, reduced Nr1d2 amplitude) in a FoxP1-dependent manner. The normal even distribution of peak expression times across the day was also lost, with genes re-clustering into condensed temporal windows—reflecting a fundamental reorganization of time-of-day biological programs in muscle.

These findings establish FOXP1 as a critical mediator of cancer-induced circadian disruption in skeletal muscle. By repressing clock activators and activating clock repressors, FOXP1 rewires rhythmic gene programs away from metabolic homeostasis and toward wasting pathways. This suggests that targeting FOXP1 or restoring circadian integrity in muscle could represent novel strategies to prevent or treat cancer cachexia.