Pancreatic Adenocarcinoma Therapeutic Targets Revealed by Tumor-Stroma Cross-Talk Analyses in Patient-Derived Xenografts
Authors: Celine Loncle
Benjamin Bian
Martin Bigonnet
Nabila Elarouci
Jean-Luc Raoul
Anthony Goncalves
Jonathan Garnier
Marine Barraud-Blanc
Fabienne Guillaumond
Jean-Robert Delpero
Jacques Ewald
Mehdi Ouaissi
Sophie Vasseur
Veronique Secq
Gwen Lomberk
Lucile Armenoult
Marion Rubis
Marine Gilabert
Vincent Moutardier
Jean-Marie Boher
Juan Iovanna
Mohamed Gasmi
Raul Urrutia
Nelson Dusetti
Pauline Duconseil
Emmanuelle Norguet
Rémy Nicolle
Julie Roques
Olivier Turrini
Odile Gayet
Marc Giovannini
Yuna Blum
Aurélien de Reyniès
Philippe Grandval
Ezequiel Calvo
Mira Ayadi
Aurélie Maignan
Erwan Bories
Flora Poizat
Laetitia Marisa
Stephane Garcia
Journal: Cell Reports (2017)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: genomics; molecular subtypes; pancreatic ductal adenocarcinoma; patient-derived xenograft; transcriptomics
Affiliations: Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre le Cancer, Paris, France. Electronic address: ., Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre le Cancer, Paris, France., Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Institut Paoli-Calmettes, Aix Marseille Université, Marseille, France., Hôpital Nord, Marseille, France; Aix Marseille Université, Marseille, France., Aix Marseille Université, Marseille, France; Institut Paoli-Calmettes, Marseille, France., Institut Paoli-Calmettes, Marseille, France., Hôpital Nord, Marseille, France., Division of Research, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI 53226, USA., Aix Marseille Université, Marseille, France; Hôpital de la Timone, Marseille, France., Hôpital de la Timone, Marseille, France., Centre Génomique du Centre de Recherche du CHUL Research Center, Ville de Québec, QC, Canada., Division of Research, Department of Surgery, Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA., Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Institut Paoli-Calmettes, Aix Marseille Université, Marseille, France. Electronic address: .

Abstract:  Preclinical models based on patient-derived xenografts have remarkable specificity in distinguishing transformed human tumor cells from non-transformed murine stromal cells computationally. We obtained 29 pancreatic ductal adenocarcinoma (PDAC) xenografts from either resectable or non-resectable patients (surgery and endoscopic ultrasound-guided fine-needle aspirate, respectively). Extensive multiomic profiling revealed two subtypes with distinct clinical outcomes. These subtypes uncovered specific alterations in DNA methylation and transcription as well as in signaling pathways involved in tumor-stromal cross-talk. The analysis of these pathways indicates therapeutic opportunities for targeting both compartments and their interactions. In particular, we show that inhibiting NPC1L1 with Ezetimibe, a clinically available drug, might be an efficient approach for treating pancreatic cancers. These findings uncover the complex and diverse interplay between PDAC tumors and the stroma and demonstrate the pivotal role of xenografts for drug discovery and relevance to PDAC. 

Retracted: No

PubPeer comments:
 It seems as if there may be a repeated image in Figure 6E. Could the authors please check? *** ![file] , 
 Dear Actinopolyspora biskrensis, Thank you very much for pointing out the mistake of our paper. We have carefully checked the raw data and found that this two duplicated pictures was a mistake of paste during figure assembly. According to the raw data, the picture in Figure 6E Vehicle Day 3 was right, while the picture in Figure 6E Ezetimibe Day 1 was mistakenly used. Please see the right picture after correction below. We regret that we did not catch this error during revisions and proofing processes. We apologize for this any confusion caused by this unintentional error sooner. Thank you again for your kindly reminder! Best Regards Juan Iovanna ![file] ,