title: Pregnane X-receptor promotes stem cell-mediated colon cancer relapse.
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.
authors.affiliation: CNRS UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France.|INSERM U1191, Montpellier, France.|Université Montpellier, Montpellier, France.
authors.forename: Chris
authors.initials: C
authors.lastname: Planque
authors.affiliation: CNRS UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France.|INSERM U1191, Montpellier, France.|Université Montpellier, Montpellier, France.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Rajabi
authors.affiliation: CNRS UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France.|INSERM U1191, Montpellier, France.|Université Montpellier, Montpellier, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Grillet
authors.affiliation: Centre de Recherche en Cancérologie de Marseille, INSERM UMR1068, CNRS UMR725, Marseille, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Finetti
authors.affiliation: Centre de Recherche en Cancérologie de Marseille, INSERM UMR1068, CNRS UMR725, Marseille, France.
authors.forename: François
authors.initials: F
authors.lastname: Bertucci
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d'Investigaciones Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Meritxell
authors.initials: M
authors.lastname: Gironella
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d'Investigaciones Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Lozano
authors.affiliation: CNRS UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France.|INSERM U1191, Montpellier, France.|Université Montpellier, Montpellier, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Beucher
authors.affiliation: CNRS UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France.|INSERM U1191, Montpellier, France.|Université Montpellier, Montpellier, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Giraud
authors.affiliation: Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Garambois
authors.affiliation: Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Vincent
authors.affiliation: Department of Pathology, University of Melbourne, Parkville, Australia.
authors.forename: Daniel
authors.initials: D
authors.lastname: Brown
authors.affiliation: CNRS UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France.|INSERM U1191, Montpellier, France.|Université Montpellier, Montpellier, France.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Caillo
authors.affiliation: Laboratoire de Biochimie, CHU Carémeau, Nîmes, France.
authors.forename: Jovana
authors.initials: J
authors.lastname: Kantar
authors.affiliation: Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.
authors.forename: André
authors.initials: A
authors.lastname: Pelegrin
authors.affiliation: Service de Chirurgie Digestive, CHU Carémeau, Nîmes, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Prudhomme
authors.affiliation: Service de Chirurgie Digestive, CHU Carémeau, Nîmes, France.
authors.forename: Jérémie
authors.initials: J
authors.lastname: Ripoche
authors.affiliation: Service d'Hépato-Gastroentérologie, CHU Carémeau, Nîmes, France.
authors.forename: Jean François
authors.initials: JF
authors.lastname: Bourgaux
authors.affiliation: Centre de Recherche en Cancérologie de Marseille, U1068 Inserm, Marseille, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Ginestier
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d'Investigaciones Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Antoni
authors.initials: A
authors.lastname: Castells
authors.affiliation: CNRS UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France.|INSERM U1191, Montpellier, France.|Université Montpellier, Montpellier, France.|Department of Pathology, University of Melbourne, Parkville, Australia.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Hollande
authors.affiliation: CNRS UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France.|INSERM U1191, Montpellier, France.|Université Montpellier, Montpellier, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Pannequin
authors.affiliation: CNRS UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France.|INSERM U1191, Montpellier, France.|Université Montpellier, Montpellier, France.
authors.forename: Jean Marc
authors.initials: JM
authors.lastname: Pascussi
mesh_terms: D000368:Aged; D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor; D015331:Cohort Studies; D003110:Colonic Neoplasms / Q000378:metabolism*; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009364:Neoplasm Recurrence, Local / Q000378:metabolism*; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000166:cytology*; D000077297:Pregnane X Receptor; D011379:Prognosis; D011987:Receptors, Steroid / Q000378:metabolism*; D050697:Retinal Dehydrogenase; D018874:Spheroids, Cellular / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C000625852:NR1I2 protein, human; C000625853:Nr1i2 protein, mouse; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase
keywords: PXR; cancer stem cell; colorectal cancer; tumor recurrence