# Decoding the Integrated Stress Response of Pancreatic Cancer: Identifying a Serine‐dependent Tumor Subset Under Metabolic Relationships With CAFs

## TL;DR

Researchers found a subset of pancreatic cancer cells that resist treatment by relying on serine from nearby cells, offering new therapeutic targets.

## Contribution

The study identifies a serine-dependent tumor subset and a CAF-tumor metabolic symbiosis using translatome profiling.

## Key findings

- ISR-activated cancer cells show chemoresistance and apoptosis resistance but are auxotrophic for serine.
- Low PHGDH and CBS expression correlates with improved patient survival.
- CAFs reprogram to produce serine, supporting tumor growth in amino acid-depleted environments.

## Abstract

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.

Researchers identified a pancreatic cancer subset with low global protein synthesis but heightened translation of stress‐response genes like ATF4, rendering cells resistant to chemotherapy and apoptosis. These tumors depend on serine and cysteine from surrounding cancer‐associated fibroblasts (CAFs), which shift to produce serine by curbing collagen synthesis. Low levels of serine‐synthesizing enzymes PHGDH and CBS in such tumors predict better patient survival.