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 BoherJacques 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

Research output: Contribution to journalArticle

23 Citations (Scopus)

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. Nicolle et al. present a genomic analysis of pancreatic cancer xenografts showing that tumor subtypes are defined by specific epigenetic, transcriptional, and stromal landscapes. They reveal potential therapeutic targets through analysis of signaling cross-talk between tumor and stromal cells.

Original languageEnglish (US)
Pages (from-to)2458-2470
Number of pages13
JournalCell Reports
Volume21
Issue number9
DOIs
StatePublished - Nov 28 2017
Externally publishedYes

Fingerprint

Heterografts
Tumors
Adenocarcinoma
Neoplasms
Stromal Cells
Pancreatic Neoplasms
Therapeutics
DNA Methylation
Drug Discovery
Transcription
Epigenomics
Needles
Surgery
Ultrasonics
Cells
Pharmaceutical Preparations

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Nicolle, R., Blum, Y., Marisa, L., Loncle, C., Gayet, O., Moutardier, V., ... Iovanna, J. (2017). Pancreatic Adenocarcinoma Therapeutic Targets Revealed by Tumor-Stroma Cross-Talk Analyses in Patient-Derived Xenografts. Cell Reports, 21(9), 2458-2470. https://doi.org/10.1016/j.celrep.2017.11.003

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

In: Cell Reports, Vol. 21, No. 9, 28.11.2017, p. 2458-2470.

Research output: Contribution to journalArticle

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 Reyniès, A, Dusetti, N & Iovanna, J 2017, 'Pancreatic Adenocarcinoma Therapeutic Targets Revealed by Tumor-Stroma Cross-Talk Analyses in Patient-Derived Xenografts', Cell Reports, vol. 21, no. 9, pp. 2458-2470. https://doi.org/10.1016/j.celrep.2017.11.003
Nicolle, Rémy ; Blum, Yuna ; Marisa, Laetitia ; Loncle, Celine ; Gayet, Odile ; Moutardier, Vincent ; Turrini, Olivier ; Giovannini, Marc ; Bian, Benjamin ; Bigonnet, Martin ; Rubis, Marion ; Elarouci, Nabila ; Armenoult, Lucile ; Ayadi, Mira ; Duconseil, Pauline ; Gasmi, Mohamed ; Ouaissi, Mehdi ; Maignan, Aurélie ; Lomberk, Gwen ; Boher, Jean Marie ; Ewald, Jacques ; Bories, Erwan ; Garnier, Jonathan ; Goncalves, Anthony ; Poizat, Flora ; Raoul, Jean Luc ; Secq, Veronique ; Garcia, Stephane ; Grandval, Philippe ; Barraud-Blanc, Marine ; Norguet, Emmanuelle ; Gilabert, Marine ; Delpero, Jean Robert ; Roques, Julie ; Calvo, Ezequiel ; Guillaumond, Fabienne ; Vasseur, Sophie ; Urrutia, Raul ; de Reyniès, Aurélien ; Dusetti, Nelson ; Iovanna, Juan. / Pancreatic Adenocarcinoma Therapeutic Targets Revealed by Tumor-Stroma Cross-Talk Analyses in Patient-Derived Xenografts. In: Cell Reports. 2017 ; Vol. 21, No. 9. pp. 2458-2470.
@article{5705557c9c3f4674b6e1b53d025fd3c0,
title = "Pancreatic Adenocarcinoma Therapeutic Targets Revealed by Tumor-Stroma Cross-Talk Analyses in Patient-Derived Xenografts",
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. Nicolle et al. present a genomic analysis of pancreatic cancer xenografts showing that tumor subtypes are defined by specific epigenetic, transcriptional, and stromal landscapes. They reveal potential therapeutic targets through analysis of signaling cross-talk between tumor and stromal cells.",
keywords = "genomics, molecular subtypes, pancreatic ductal adenocarcinoma, patient-derived xenograft, transcriptomics, tumor microenvironment",
author = "R{\'e}my Nicolle and Yuna Blum and Laetitia Marisa and Celine Loncle and Odile Gayet and Vincent Moutardier and Olivier Turrini and Marc Giovannini and Benjamin Bian and Martin Bigonnet and Marion Rubis and Nabila Elarouci and Lucile Armenoult and Mira Ayadi and Pauline Duconseil and Mohamed Gasmi and Mehdi Ouaissi and Aur{\'e}lie Maignan and Gwen Lomberk and Boher, {Jean Marie} and Jacques Ewald and Erwan Bories and Jonathan Garnier and Anthony Goncalves and Flora Poizat and Raoul, {Jean Luc} and Veronique Secq and Stephane Garcia and Philippe Grandval and Marine Barraud-Blanc and Emmanuelle Norguet and Marine Gilabert and Delpero, {Jean Robert} and Julie Roques and Ezequiel Calvo and Fabienne Guillaumond and Sophie Vasseur and Raul Urrutia and {de Reyni{\`e}s}, Aur{\'e}lien and Nelson Dusetti and Juan Iovanna",
year = "2017",
month = "11",
day = "28",
doi = "10.1016/j.celrep.2017.11.003",
language = "English (US)",
volume = "21",
pages = "2458--2470",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "9",

}

TY - JOUR

T1 - Pancreatic Adenocarcinoma Therapeutic Targets Revealed by Tumor-Stroma Cross-Talk Analyses in Patient-Derived Xenografts

AU - Nicolle, Rémy

AU - Blum, Yuna

AU - Marisa, Laetitia

AU - Loncle, Celine

AU - Gayet, Odile

AU - Moutardier, Vincent

AU - Turrini, Olivier

AU - Giovannini, Marc

AU - Bian, Benjamin

AU - Bigonnet, Martin

AU - Rubis, Marion

AU - Elarouci, Nabila

AU - Armenoult, Lucile

AU - Ayadi, Mira

AU - Duconseil, Pauline

AU - Gasmi, Mohamed

AU - Ouaissi, Mehdi

AU - Maignan, Aurélie

AU - Lomberk, Gwen

AU - Boher, Jean Marie

AU - Ewald, Jacques

AU - Bories, Erwan

AU - Garnier, Jonathan

AU - Goncalves, Anthony

AU - Poizat, Flora

AU - Raoul, Jean Luc

AU - Secq, Veronique

AU - Garcia, Stephane

AU - Grandval, Philippe

AU - Barraud-Blanc, Marine

AU - Norguet, Emmanuelle

AU - Gilabert, Marine

AU - Delpero, Jean Robert

AU - Roques, Julie

AU - Calvo, Ezequiel

AU - Guillaumond, Fabienne

AU - Vasseur, Sophie

AU - Urrutia, Raul

AU - de Reyniès, Aurélien

AU - Dusetti, Nelson

AU - Iovanna, Juan

PY - 2017/11/28

Y1 - 2017/11/28

N2 - 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. Nicolle et al. present a genomic analysis of pancreatic cancer xenografts showing that tumor subtypes are defined by specific epigenetic, transcriptional, and stromal landscapes. They reveal potential therapeutic targets through analysis of signaling cross-talk between tumor and stromal cells.

AB - 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. Nicolle et al. present a genomic analysis of pancreatic cancer xenografts showing that tumor subtypes are defined by specific epigenetic, transcriptional, and stromal landscapes. They reveal potential therapeutic targets through analysis of signaling cross-talk between tumor and stromal cells.

KW - genomics

KW - molecular subtypes

KW - pancreatic ductal adenocarcinoma

KW - patient-derived xenograft

KW - transcriptomics

KW - tumor microenvironment

UR - http://www.scopus.com/inward/record.url?scp=85035748327&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85035748327&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2017.11.003

DO - 10.1016/j.celrep.2017.11.003

M3 - Article

C2 - 29186684

AN - SCOPUS:85035748327

VL - 21

SP - 2458

EP - 2470

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 9

ER -