Decoding the Integrated Stress Response of Pancreatic Cancer: Identifying a Serine‐dependent Tumor Subset Under Metabolic Relationships With CAFs.
Open accessPublished version of a preprint
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.
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Cites
Global quantification of mammalian gene expression control
Schwanhäusser, B., Busse, D., Li, N., Dittmar, G., Schuchhardt, J., Wolf, J., Chen, W., & Selbach, M. (2011) · Nature · doi:10.1038/nature10098 · Cited by 6,566 · see citing works
Stratification of pancreatic ductal adenocarcinomas based on tumor and microenvironment features
Puleo, F., Nicolle, R., Blum, Y., Cros, J., Marisa, L., Demetter, P., Quertinmont, E., Svrcek, M., Elarouci, N., Iovanna, J., et al. (2018) · Gastroenterology · doi:10.1053/j.gastro.2018.08.033 · Cited by 563 · see citing works
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- Authors
- Shin, S., Liauzun, M., Solorzano, J., Bras, M. L., Jean, C., Fourneaux, B., Dore, M., Fevrier, L., Belhabib, I., Brunel, A., Neuzillet, C., Larroque, M., Joffre, C., Rocchi, S., Fraunhoffer, N., Perraud, A., Mathonnet, M., Pancaldi, V., Linares, L., Iovanna, J., Dusetti, N., Larsson, O., Nicolle, R., Pyronnet, S., Bousquet, C., & Martineau, Y.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Cancer Research Center of Toulouse (CRCT) INSERM U1037 ERL5294 CNRS University of Toulouse Toulouse France
- Inserm (FR)
- Université de Versailles Saint-Quentin-en-Yvelines (FR)
- Centre Méditerranéen de Médecine Moléculaire INSERM U1065 Université Cote d'Azur Nice France
- Department of Digestive Surgery Faculty of Medicine University Hospital of Limoges and INSERM U1308 – CAPTuR University of Limoges Limoges France
- Karolinska Institutet (SE)
- Centre de Recherche sur l'Inflammation (CRI) INSERM U1149 CNRS ERL 8252 Université Paris Cité Paris France
- Corresponding author
- Martineau, Yvan
- ORCID
- Venue
- Advanced Science
- Publisher
- Wiley
- Published
- 2026-02-17
- Volume
- 13
- Issue
- 18
- Pages
- e15740-e15740
- ISSN
- 2198-3844 (ISSN-L)
- PMC
- PMC13042921
- OpenAlex
- W7130396247
- Cited by
- 0
- References
- 2
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Advanced Science (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- HAL (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Agence Nationale de la Recherche (ANR_SubRnaAct_to_YM)
- Fondation ARC pour la Recherche sur le Cancer (Pancreas2024_to_CB, Pancreas2025_to_YM)
- Vetenskapsrådet (2020‐01665_to_OL)
- Cancerfonden (222186_to_OL)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- pancreatic ductal adenocarcinoma, integrated stress response, cancer-associated fibroblasts, protein synthesis, PHGDH, cysteine biosynthesis, ATF4, chemoresistance, apoptosis resistance, tumor microenvironment metabolism, patient-derived xenografts, overall survival
- MeSH terms
- Cancer-Associated Fibroblasts, Metabolic Reprogramming, Integrated Stress Response, Animals, Female, Humans, Pancreatic Neoplasms, Serine, Stress, Physiological, Gene Expression Regulation, Neoplastic, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Mice
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