Mitophagy‑Competent Cancer‑Associated Fibroblasts Fuel Chemoresistance by Rewiring Pyrimidine Metabolism in Pancreatic Cancer - PubMed
2 hours ago
- #chemoresistance
- #pyrimidine metabolism
- #mitophagy
- Mitophagy-competent CAFs drive gemcitabine resistance in pancreatic cancer by altering pyrimidine metabolism.
- ZEB1 is upregulated in resistant CAFs via SETD1A-mediated H3K4 methylation, promoting BNIP3-mediated mitophagy.
- CAFs secrete nucleotides that inhibit gemcitabine uptake and supply pyrimidine metabolism substrates to cancer cells.
- ZEB1 activates CXCL8, engaging the CXCR1/2-MEK/ERK pathway in tumor cells to boost pyrimidine metabolism via RRM1/E2F1/G6PD.
- Combined inhibition of CXCR1/2 or G6PD with gemcitabine restores chemosensitivity and suppresses tumor growth in models.