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Translatome-based classification reveals a dual metabolic dependency of a new tumor subtype of pancreatic cancer

Sauyeun Shin, Remy Nicolle, View ORCID ProfileChristine Jean, Remi Samain, Mira Ayadi, Jerome Raffenne, Alexia Brunel, Jacobo Solorzano, Cindy Neuzillet, Carine Joffre, Stephane Rocchi, Juan Iovanna, Nelson Dusetti, Ola Larsson, Stephane Pyronnet, View ORCID ProfileCorinne Bousquet, View ORCID ProfileYvan Martineau
doi: https://doi.org/10.1101/2020.12.23.424227
Sauyeun Shin
1Centre de Recherche en Cancérologie de Toulouse (CRCT), INSERM U1037, Université Toulouse III Paul Sabatier, ERL5294 CNRS, Toulouse, France; Equipe labellisée Ligue Contre Le Cancer, Laboratoire d’excellence LABEX TOUCAN.
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Remy Nicolle
2Programme Cartes d’Identité des Tumeurs (CIT), Ligue Nationale Contre Le Cancer, Paris, France
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Christine Jean
1Centre de Recherche en Cancérologie de Toulouse (CRCT), INSERM U1037, Université Toulouse III Paul Sabatier, ERL5294 CNRS, Toulouse, France; Equipe labellisée Ligue Contre Le Cancer, Laboratoire d’excellence LABEX TOUCAN.
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Remi Samain
1Centre de Recherche en Cancérologie de Toulouse (CRCT), INSERM U1037, Université Toulouse III Paul Sabatier, ERL5294 CNRS, Toulouse, France; Equipe labellisée Ligue Contre Le Cancer, Laboratoire d’excellence LABEX TOUCAN.
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Mira Ayadi
2Programme Cartes d’Identité des Tumeurs (CIT), Ligue Nationale Contre Le Cancer, Paris, France
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Jerome Raffenne
1Centre de Recherche en Cancérologie de Toulouse (CRCT), INSERM U1037, Université Toulouse III Paul Sabatier, ERL5294 CNRS, Toulouse, France; Equipe labellisée Ligue Contre Le Cancer, Laboratoire d’excellence LABEX TOUCAN.
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Alexia Brunel
1Centre de Recherche en Cancérologie de Toulouse (CRCT), INSERM U1037, Université Toulouse III Paul Sabatier, ERL5294 CNRS, Toulouse, France; Equipe labellisée Ligue Contre Le Cancer, Laboratoire d’excellence LABEX TOUCAN.
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Jacobo Solorzano
1Centre de Recherche en Cancérologie de Toulouse (CRCT), INSERM U1037, Université Toulouse III Paul Sabatier, ERL5294 CNRS, Toulouse, France; Equipe labellisée Ligue Contre Le Cancer, Laboratoire d’excellence LABEX TOUCAN.
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Cindy Neuzillet
3Medical Oncology Department, Curie Institute, Versailles Saint-Quentin University, Saint-Cloud, France
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Carine Joffre
1Centre de Recherche en Cancérologie de Toulouse (CRCT), INSERM U1037, Université Toulouse III Paul Sabatier, ERL5294 CNRS, Toulouse, France; Equipe labellisée Ligue Contre Le Cancer, Laboratoire d’excellence LABEX TOUCAN.
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Stephane Rocchi
4Centre Méditerranéen de Médecine Moléculaire, INSERM U1065, Université Cote d’Azur, Nice, France
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Juan Iovanna
5Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille Université, Marseille, France
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Nelson Dusetti
5Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille Université, Marseille, France
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Ola Larsson
6Department of Oncology-Pathology, Karolinska Institutet, Stockholm 171 76, Sweden
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Stephane Pyronnet
1Centre de Recherche en Cancérologie de Toulouse (CRCT), INSERM U1037, Université Toulouse III Paul Sabatier, ERL5294 CNRS, Toulouse, France; Equipe labellisée Ligue Contre Le Cancer, Laboratoire d’excellence LABEX TOUCAN.
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Corinne Bousquet
1Centre de Recherche en Cancérologie de Toulouse (CRCT), INSERM U1037, Université Toulouse III Paul Sabatier, ERL5294 CNRS, Toulouse, France; Equipe labellisée Ligue Contre Le Cancer, Laboratoire d’excellence LABEX TOUCAN.
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Yvan Martineau
1Centre de Recherche en Cancérologie de Toulouse (CRCT), INSERM U1037, Université Toulouse III Paul Sabatier, ERL5294 CNRS, Toulouse, France; Equipe labellisée Ligue Contre Le Cancer, Laboratoire d’excellence LABEX TOUCAN.
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  • For correspondence: yvan.martineau@inserm.fr
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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.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted December 24, 2020.
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Translatome-based classification reveals a dual metabolic dependency of a new tumor subtype of pancreatic cancer
Sauyeun Shin, Remy Nicolle, Christine Jean, Remi Samain, Mira Ayadi, Jerome Raffenne, Alexia Brunel, Jacobo Solorzano, Cindy Neuzillet, Carine Joffre, Stephane Rocchi, Juan Iovanna, Nelson Dusetti, Ola Larsson, Stephane Pyronnet, Corinne Bousquet, Yvan Martineau
bioRxiv 2020.12.23.424227; doi: https://doi.org/10.1101/2020.12.23.424227
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Translatome-based classification reveals a dual metabolic dependency of a new tumor subtype of pancreatic cancer
Sauyeun Shin, Remy Nicolle, Christine Jean, Remi Samain, Mira Ayadi, Jerome Raffenne, Alexia Brunel, Jacobo Solorzano, Cindy Neuzillet, Carine Joffre, Stephane Rocchi, Juan Iovanna, Nelson Dusetti, Ola Larsson, Stephane Pyronnet, Corinne Bousquet, Yvan Martineau
bioRxiv 2020.12.23.424227; doi: https://doi.org/10.1101/2020.12.23.424227

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