Decoding the Integrated Stress Response of Pancreatic Cancer: Identifying a Serine-dependent Tumor Subset Under...

Pancreatic ductal adenocarcinoma (PDA) transcriptomic profiling has identified prognostic subtypes, yet patient-specific first-line therapies remain elusive. Here, we stratified PDA tumors by mRNA translation rates, a frequently dysregulated step in gene expression, using translatome profiling of 27 patient-derived xenografts (PDXs). Unsupervised analysis revealed a distinct tumor subset with low global protein synthesis but sustained translation of Integrated Stress Response (ISR) mRNAs, including ATF4. These ISR-activated cancer cells exhibited broad chemoresistance and apoptosis resistance, yet were auxotrophic for serine due to loss of PHGDH and CBS expression, impairing serine and cysteine biosynthesis. This vulnerability correlated with improved overall survival in patients with low expression of both enzymes. Notably, cancer-associated fibroblasts (CAFs) reprogrammed by ISR-activated cells, shifting from myCAF to iCAF phenotype with reduced collagen synthesis and glycine-to-serine conversion, produced serine and sustained tumor growth in amino acid-depleted environments. Our findings demonstrate the power of translatome profiling to reveal stable, drug-resistant PDA cell states and identify a targetable CAF-tumor metabolic symbiosis, opening new avenues for therapeutic intervention in this highly lethal malignancy.