Pancreatic Adenocarcinoma Therapeutic Targets Revealed by Tumor-Stroma Cross-Talk Analyses in Patient-Derived Xenografts

Remy Nicolle 1, 2, * Yuna Blum 1, 2 Laëtitia Marisa 2, 1 Céline Loncle 3 Odile Gayet 4, 3 Vincent Moutardier 4, 5 Olivier Turrini 6, 4 Marc Giovannini 6 Benjamin Bian 3 Martin Bigonnet 3 Marion Rubis 3 Nabila Elarouci 7 Lucile Armenoult 7 Mira Ayadi 7 Pauline Duconseil 3 Mohamed Gasmi 5 Mehdi Ouaïssi 6 Aurélie Maignan 3 Gwen Lomberk 8 Jean-Marie Boher 6 Jacques Ewald 6 Erwan Bories 6 Jonathan Garnier 3 Anthony Gonçalves 6, 4 Flora Poizat 6 Jean-Luc Raoul 6, 4 Veronique Secq 3, 5 Stéphane Garcia 5 Philippe Grandval 4, 9 Marine Barraud-Blanc 10 Emmanuelle Norguet 10 Marine Gilabert 6 Jean-Robert Delpero 6, 4 Julie Roques 3 Ezequiel Calvo 10 Fabienne Guillaumond 3 Sophie Vasseur 3 Raul Urrutia 8 Aurélien de Reyniès 11 Nelson Dusetti 3 Juan Iovanna 3, *
* Corresponding author
1 Ligue Nationale Contre le Cancer - Paris
2 CIT - (le programme) Cartes d'identité des tumeurs
3 CRCM - Centre de Recherche en Cancérologie de Marseille
4 AMU - Aix Marseille Université
5 Hôpital Nord [CHU - APHM]
6 Institut Paoli-Calmettes
7 Programme Cartes d'Identité des Tumeurs (CIT)
8 University of Wisconsin School of Medicine and Public Health
9 TIMONE - Hôpital de la Timone [CHU - APHM]
10 Centre Hospitalier Université Laval (CHUL), Quebec
11 CIT - Programme"Cartes d'Identité des Tumeurs "
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.
Keywords : molecular subtypes pancreatic ductal adenocarcinoma genomics patient-derived xenograft transcriptomics tumor microenvironment
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Remy Nicolle, Yuna Blum, Laëtitia Marisa, Céline Loncle, Odile Gayet, et al.. Pancreatic Adenocarcinoma Therapeutic Targets Revealed by Tumor-Stroma Cross-Talk Analyses in Patient-Derived Xenografts. Cell Reports , Elsevier Inc, 2017, 21 (9), pp.2458-2470. ⟨10.1016/j.celrep.2017.11.003⟩. ⟨inserm-01985259⟩

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