Background: Cancer cachexia is a complex metabolic disorder that includes progressive muscle wasting and loss of fat stores. Though cachexia accounts for 30-40% of cancer-related deaths, currently there are no established treatment for cancer-induced wasting. Aim: We examined whether blocking the secretion of extracellular vesicles (EVs) from tumour cells can inhibit cancer-induced cachexia.
Methodology: Cortactin (CTTN) was knocked-out (KO) using CRISPR/Cas9 technology in colon and pancreatic cancer cells. EVs were isolated and characterised by western blotting and nanoparticle tracking analysis. Co-culture and pre-clinical studies (C26 mice models) were carried out to study the cachectic phenotype.
Results: Loss of CTTN inhibited the release of EVs. While C26 wild-type (WT)-derived EVs induced atrophy in myotubes and lipolysis in adipocytes, CTTN KO-EVs did not induce atrophy or lipolysis. Proteomics analysis of EVs highlighted the enrichment of cachectic proteins in WT EVs compared to KO EVs. Follow-up C26 mice pre-clinical studies highlighted that CTTN KO tumour-bearing mice exhibited stable body weight, reduced tumour burden, and dramatically extended lifespan compared to mice bearing WT tumour. Remarkably, CTTN KO prevented tumour-induced loss of muscle, fat, and other major organs. Consistent with this, overexpression of CTTN increased EV secretion and drastically decreased the lifespan of C26 mice by accelerating tumour-induced weight loss.
Conclusion: Overall, these findings indicate that blocking EV release from tumour might be a promising approach to treat cancer-induced cachexia, improve quality of life, and extend the lifespan of cancer patients.