Translatome-based classification reveals a dual metabolic dependency of a new tumor subtype of pancreatic cancer
Open accessPreprint — published as 10.1002/advs.202515740 · Paper page
Abstract
Molecular profiling of Pancreatic Ductal Adenocarcinoma (PDA), based on transcriptomic analyses, identifies two main prognostic subtypes (basal-like and classical), but does not allow personalized first-line treatment. To date, tumors have not been profiled based on protein synthesis rates, yet the step of mRNA translation is highly deregulated in both PDA cancer cells and their microenvironment. Using a collection of twenty-seven pancreatic Patient-Derived Xenografts (PDX), we performed genome-wide analysis of translated mRNA (translatome). Unsupervised bioinformatics analysis revealed a new tumor subtype harboring a low protein synthesis rate, but associated with a robust translation of mRNAs encoding effectors of the integrated stress response (ISR), including the transcription factor ATF4. Functional characterization of the “ISR-activated” human cancer cells revealed a high resistance to drugs, low autophagic capacities, and importantly, metabolic impairments in the serine synthesis and transsulfuration pathways. Overall, our study highlights the strength of translatomic profiling on PDA, which here revealed an unforeseen drug-resistant cancer cell phenotype, whose auxotrophy to both serine and cysteine may be amenable to targeted therapy.
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Polysome Fractionation for Transcriptome-Wide Studies of mRNA Translation
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- Authors
- Shin, S., Nicolle, R., Jean, C., Samain, R., Ayadi, M., Raffenne, J., Brunel, A., Solorzano, J., Neuzillet, C., Joffre, C., Rocchi, S., Iovanna, J., Dusetti, N., Larsson, O., Pyronnet, S., Bousquet, C., & Martineau, Y.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- La Ligue Contre le Cancer (FR)
- Université de Versailles Saint-Quentin-en-Yvelines (FR)
- Karolinska Institutet (SE)
- Corresponding author
- Martineau, Yvan
- ORCID
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2020-12-24
- Pages
- 1447-1454.e4
- OpenAlex
- W3117800640
- Cited by
- 3
- References
- 54
- Citations by year
- 2025: 1 · 2022: 2
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- HAL (submittedVersion, other-oa)
- HAL (submittedVersion)
- Funders
- Institut National Du Cancer
- Région Occitanie Pyrénées-Méditerranée
- National Cancer Institute
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- pancreatic ductal adenocarcinoma, translatome, mRNA translation, integrated stress response, ATF4, serine biosynthesis, transsulfuration pathway, cysteine auxotrophy, drug resistance, autophagy, patient-derived xenografts, cancer subtyping, protein synthesis rate
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