Cell Reports
Volume 21, Issue 9, 28 November 2017, Pages 2458-2470
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Article
Pancreatic Adenocarcinoma Therapeutic Targets Revealed by Tumor-Stroma Cross-Talk Analyses in Patient-Derived Xenografts

https://doi.org/10.1016/j.celrep.2017.11.003Get rights and content
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Highlights

  • Patient xenografts are relevant models of pancreatic cancers and of their stroma

  • Xenografts allow the genomic analysis of unresectable pancreatic cancers

  • The epigenome, transcriptome, and stroma of pancreatic cancer define two subtypes

  • Pancreatic cancer is sensitive to inhibition of NPC1L1 by Ezetimibe

Summary

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

patient-derived xenograft
pancreatic ductal adenocarcinoma
genomics
transcriptomics
molecular subtypes
tumor microenvironment

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These authors contributed equally

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