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

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.

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Journal
Advanced Science
Published
2026-02-17
DOI
https://doi.org/10.1002/advs.202515740
Primary Topic
Cancer Research and Treatments
Type
article
Field-Weighted Citation Impact
0.00

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article

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

M. Mathonnet, Cindy Neuzillet, Lea Fevrier, Aurélie Perraud et al.
Advanced Science
Cancer Research and Treatments
article

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

M. Mathonnet, Cindy Neuzillet, Lea Fevrier, Aurélie Perraud, Ismahane Belhabib, Jacobo Solórzano, Alexia Brunel, Laëtitia K. Linares, Mehdi Liauzun, Nicolás A. Fraunhoffer, Ola Larsson, Sauyeun Shin, Corinne Bousquet, J. Iovanna, S. Rocchi, Benjamin Fourneaux, Yvan Martineau, Morgane Le Bras, R. Nicolle, Nelson Dusetti, Christine Jean, Larroque Marion, Carine Joffre, Vera Pancaldi, Margaux Dore, Stephane Pyronnet
article en

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.

Advanced ScienceVol. 13(18)
Centre National de la Recherche Scientifique (FR), Inserm (FR), Université de Versailles Saint-Quentin-en-Yvelines (FR), Université Paris Cité (FR), Karolinska Institutet (SE), Centre de Recherches en Cancérologie de Toulouse (FR), La Ligue Contre le Cancer (FR), Laboratoire d'Aérologie (FR), Centre Méditerranéen de Médecine Moléculaire (FR), Centre de Recherche sur l'Inflammation (FR), Institut de Recherche en Cancérologie de Montpellier (FR), Centre de Recherche en Cancérologie de Marseille (FR), Université de Limoges (FR)
Agence Nationale de la Recherche, Fondation ARC pour la Recherche sur le Cancer, Centre National de la Recherche Scientifique, Deutschen Konsortium für Translationale Krebsforschung, H. Lundbeck A/S, Région Occitanie Pyrénées-Méditerranée
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Cancer Research and Treatments
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