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Pancreatic Adenocarcinoma Therapeutic Targets Revealed by Tumor-Stroma Cross-Talk Analyses in Patient-Derived Xenografts. Cell Rep 2017 Nov 28;21(9):2458-2470 PMID: 29186684 PMCID: PMC6082139

Pubmed ID

29186684

DOI

10.1016/j.celrep.2017.11.003

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.

Author List

Nicolle R, Blum Y, Marisa L, Loncle C, Gayet O, Moutardier V, Turrini O, Giovannini M, Bian B, Bigonnet M, Rubis M, Elarouci N, Armenoult L, Ayadi M, Duconseil P, Gasmi M, Ouaissi M, Maignan A, Lomberk G, Boher JM, Ewald J, Bories E, Garnier J, Goncalves A, Poizat F, Raoul JL, Secq V, Garcia S, Grandval P, Barraud-Blanc M, Norguet E, Gilabert M, Delpero JR, Roques J, Calvo E, Guillaumond F, Vasseur S, Urrutia R, de Reyni├Ęs A, Dusetti N, Iovanna J

Authors

Gwen Lomberk PhD Associate Professor in the Surgery department at Medical College of Wisconsin
Raul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of Wisconsin




Scopus

2-s2.0-85035748327   13 Citations

MESH terms used to index this publication - Major topics in bold

Animals
Carcinoma, Pancreatic Ductal
Cell Transformation, Neoplastic
Datasets as Topic
Ezetimibe
Humans
Male
Mice
Pancreatic Neoplasms
Spheroids, Cellular
Xenograft Model Antitumor Assays
jenkins-FCD Prod-310 bff9d975ec7f2d302586822146c2801dd4449aad