Decoding the Integrated Stress Response of Pancreatic Cancer: Identifying a Serine-dependent Tumor Subset Under Metabolic Relationships With CAFs - PubMed
4 days ago
- #therapeutic targets
- #pancreatic cancer
- #metabolic symbiosis
- Pancreatic ductal adenocarcinoma (PDA) was studied using translatome profiling of 27 patient-derived xenografts (PDXs).
- A distinct tumor subset with low global protein synthesis but sustained translation of Integrated Stress Response (ISR) mRNAs, including ATF4, was identified.
- ISR-activated cancer cells showed broad chemoresistance and apoptosis resistance but were auxotrophic for serine due to loss of PHGDH and CBS expression.
- Low expression of PHGDH and CBS correlated with improved overall survival in patients.
- Cancer-associated fibroblasts (CAFs) reprogrammed by ISR-activated cells shifted from myCAF to iCAF phenotype, producing serine and sustaining tumor growth.
- The study highlights a targetable CAF-tumor metabolic symbiosis, offering new therapeutic avenues for pancreatic cancer.