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

Rémy Nicolle; Yuna Blum; Laetitia Marisa; Celine Loncle; Odile Gayet; Vincent Moutardier; Olivier Turrini; Marc Giovannini; Benjamin Bian; Martin Bigonnet; Marion Rubis; Nabila Elarouci; Lucile Armenoult; Mira Ayadi; Pauline Duconseil; Mohamed Gasmi; Mehdi Ouaissi; Aurélie Maignan; Gwen Lomberk; Jean-Marie Boher; Jacques Ewald; Erwan Bories; Jonathan Garnier; Anthony Goncalves; Flora Poizat; Jean-Luc Raoul; Veronique Secq; Stephane Garcia; Philippe Grandval; Marine Barraud-Blanc; Emmanuelle Norguet; Marine Gilabert; Jean-Robert Delpero; Julie Roques; Ezequiel Calvo; Fabienne Guillaumond; Sophie Vasseur; Raul Urrutia; Aurélien de Reyniès; Nelson Dusetti; Juan Iovanna

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

2017

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.

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