Fatty acid oxidation is critical for the tumorigenic potential and chemoresistance of pancreatic cancer stem cells

Autor: Marta Mascaraque, Sarah Courtois, Alba Royo-García, David Barneda, Andrei M. Stoian, Isabel Villaoslada, Pilar Espiau-Romera, Ansooya Bokil, Andrés Cano-Galiano, Petra Jagust, Christopher Heeschen, Patricia Sancho
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: Journal of Translational Medicine, Vol 22, Iss 1, Pp 1-18 (2024)
Druh dokumentu: article
ISSN: 1479-5876
DOI: 10.1186/s12967-024-05598-6
Popis: Abstract Background We have previously demonstrated the significant reliance of pancreatic Cancer Stem Cells (PaCSCs) on mitochondrial oxidative phosphorylation (OXPHOS), which enables versatile substrate utilization, including fatty acids (FAs). Notably, dysregulated lipid scavenging and aberrant FA metabolism are implicated in PDAC progression. Methods & results Our bioinformatics analyses revealed elevated expression of lipid metabolism-related genes in PDAC tissue samples compared to normal tissue samples, which correlated with a stemness signature. Additionally, PaCSCs exhibited heightened expression of diverse lipid metabolism genes and increased lipid droplet accumulation compared to differentiated progenies. Treatment with palmitic, oleic, and linolenic FAs notably augmented the self-renewal and chemotherapy resistance of CD133+ PaCSCs. Conversely, inhibitors of FA uptake, storage and metabolism reduced CSC populations both in vitro and in vivo. Mechanistically, inhibition of FA metabolism suppressed OXPHOS activity, inducing energy depletion and subsequent cell death in PaCSCs. Importantly, combining a FAO inhibitor and Gemcitabine treatment enhanced drug efficacy in vitro and in vivo, effectively diminishing the CSC content and functionality. Conclusion Targeting FAO inhibition represents a promising therapeutic strategy against this highly tumorigenic population.
Databáze: Directory of Open Access Journals
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje