Oncotarget

Research Papers:

Pregnane X-receptor promotes stem cell-mediated colon cancer relapse

Chris Planque, Fatemeh Rajabi, Fanny Grillet, Pascal Finetti, François Bertucci, Meritxell Gironella, Juan José Lozano, Bertrand Beucher, Julie Giraud, Véronique Garambois, Charles Vincent, Daniel Brown, Ludovic Caillo, Jovana Kantar, André Pelegrin, Michel Prudhomme, Jérémie Ripoche, Jean François Bourgaux, Christophe Ginestier, Antoni Castells, Frédéric Hollande _, Julie Pannequin and Jean Marc Pascussi

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Oncotarget. 2016; 7:56558-56573. https://doi.org/10.18632/oncotarget.10646

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Abstract

Chris Planque1,2,3,*, Fatemeh Rajabi1,2,3,*, Fanny Grillet1,2,3, Pascal Finetti4, François Bertucci4, Meritxell Gironella5, Juan José Lozano5, Bertrand Beucher1,2,3, Julie Giraud1,2,3, Véronique Garambois6, Charles Vincent6, Daniel Brown7, Ludovic Caillo1,2,3, Jovana Kantar8, André Pelegrin6, Michel Prudhomme9, Jérémie Ripoche9, Jean François Bourgaux10, Christophe Ginestier11, Antoni Castells5, Frédéric Hollande1,2,3,7,#, Julie Pannequin1,2,3,#, Jean Marc Pascussi1,2,3,#

1CNRS UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France

2INSERM U1191, Montpellier, France

3Université Montpellier, Montpellier, France

4Centre de Recherche en Cancérologie de Marseille, INSERM UMR1068, CNRS UMR725, Marseille, France

5Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d'Investigaciones Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

6Institut de Recherche en Cancérologie de Montpellier, Montpellier, France

7Department of Pathology, University of Melbourne, Parkville, Australia

8Laboratoire de Biochimie, CHU Carémeau, Nîmes, France

9Service de Chirurgie Digestive, CHU Carémeau, Nîmes, France

10Service d’Hépato-Gastroentérologie, CHU Carémeau, Nîmes, France

11Centre de Recherche en Cancérologie de Marseille, U1068 Inserm, Marseille, France

*These authors have contributed equally to this work

#These authors jointly supervised the work

Correspondence to:

Frédéric Hollande, email: [email protected]

Jean Marc Pascussi, email: [email protected]

Keywords: PXR, colorectal cancer, cancer stem cell, tumor recurrence

Received: March 23, 2016     Accepted: May 29, 2016     Published: July 18, 2016

ABSTRACT

Colorectal cancer lethality usually results from post-treatment relapse in the majority of stage II-IV patients, due to the enhanced resistance of Cancer Stem Cells (CSCs). Here, we show that the nuclear receptor Pregnane X Receptor (PXR, NR1I2), behaves as a key driver of CSC-mediated tumor recurrence. First, PXR is specifically expressed in CSCs, where it drives the expression of genes involved in self-renewal and chemoresistance. Clinically, high levels of PXR correlate with poor recurrence-free survival in a cohort of >200 stage II/III colorectal cancer patients treated with chemotherapy, for whom finding biomarkers of treatment outcome is an urgent clinical need. shRNA silencing of PXR increased the chemo-sensitivity of human colon CSCs, reduced their self-renewal and tumor-initiating potential, and drastically delayed tumor recurrence in mice following chemotherapy. This study uncovers PXR as a key factor for CSC self-renewal and chemoresistance and targeting PXR thus represents a promising strategy to minimize colorectal cancer relapse by selectively sensitizing CSCs to chemotherapy.


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