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

// Chris Planque 1, 2, 3, * , Fatemeh Rajabi 1, 2, 3, * , Fanny Grillet 1, 2, 3 , Pascal Finetti 4 , François Bertucci 4 , Meritxell Gironella 5 , Juan José Lozano 5 , Bertrand Beucher 1, 2, 3 , Julie Giraud 1, 2, 3 , Véronique Garambois 6 , Charles Vincent 6 , Daniel Brown 7 , Ludovic Caillo 1, 2, 3 , Jovana Kantar 8 , André Pelegrin 6 , Michel Prudhomme 9 , Jérémie Ripoche 9 , Jean François Bourgaux 10 , Christophe Ginestier 11 , Antoni Castells 5 , Frédéric Hollande 1, 2, 3, 7, # , Julie Pannequin 1, 2, 3, # , Jean Marc Pascussi 1, 2, 3, # 1 CNRS UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France 2 INSERM U1191, Montpellier, France 3 Université Montpellier, Montpellier, France 4 Centre de Recherche en Cancérologie de Marseille, INSERM UMR1068, CNRS UMR725, Marseille, France 5 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d'Investigaciones Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain 6 Institut de Recherche en Cancérologie de Montpellier, Montpellier, France 7 Department of Pathology, University of Melbourne, Parkville, Australia 8 Laboratoire de Biochimie, CHU Carémeau, Nîmes, France 9 Service de Chirurgie Digestive, CHU Carémeau, Nîmes, France 10 Service d’Hépato-Gastroentérologie, CHU Carémeau, Nîmes, France 11 Centre 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: frederic.hollande@unimelb.edu.au Jean Marc Pascussi, email: jean-marc.pascussi@inserm.fr 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.