Deciphering molecular crosstalk mechanisms between skeletal muscle atrophy and KRAS-mutant pancreatic cancer: a literature review.

BACKGROUND AND

OBJECTIVE

Cachexia-induced skeletal muscle atrophy is a critical manifestation in Kirsten rat sarcoma viral oncogene homologue (KRAS)-mutant pancreatic cancer (PC) patients, predominantly characterized by a shift in metabolic equilibrium towards catabolism that accelerates protein degradation in myofibers and leads to muscle atrophy. This metabolic reprogramming not only supports tumor growth but also precipitates energy depletion in skeletal muscle tissues. Exploring these mechanisms reveals potential therapeutic targets in the metabolic and proteolytic pathways associated with KRAS-mutant PC.

METHODS

A comprehensive search for literature was conducted in PubMed, Web of Science, Google Scholar and other search engines up to May 21st, 2024. Studies on PC models and patients were included.

KEY CONTENT AND FINDINGS: The crosstalk between KRAS-mutant PC and skeletal muscle atrophy can be categorized into four principal domains: (I) KRAS-driven metabolic reprogramming in cancer cells leads to the depletion of muscle energy reserves, thereby influencing the reallocation of myofiber energy towards fueling cancer cell; (II) KRAS-mutant cancer cells rely on nutrient-scavenging pathways, resulting in altered cytokine profiles, increased ubiquitin mRNA expression and autophagy-lysosome pathway, which facilitate myotube degradation and inhibit muscle regeneration, thereby disrupting muscular homeostasis and causing a one-way nutrient flux; (III) tumor-induced oxidative stress inflicts damage on myotubes, highlighting the detrimental effects of reactive oxygen species on muscle structure; (IV) KRAS-mutant cancer cells remodulate immune cell dynamics within the tumor environment, thereby reshaping host immunity. Together, these findings illuminate the intricate interplay between KRAS-mutant PC and skeletal muscle atrophy, mapping the pathophysiological framework that is crucial for understanding sarcopenia and related disorders.

CONCLUSIONS

This comprehensive analysis advances our understanding of the complex etiology of cancer cachexia and stimulates the development of targeted therapeutic strategies.