Prostatic luminal progenitor cells: from physiology to cancer

ED BIO SORBONNE PARIS CITE
Proposition de sujet de thèse à l’appui d’une demande de contrat doctoral 2015-2016
Renseignements relatifs à l’Unité de Recherche :
Label et intitulé : Inserm U1151, Institut Necker Enfants Malades (INEM)
Nom et prénom du Directeur : Xavier NASSIF
Téléphone : 01 72 60 65 08
Télécopie : 01 72 60 65 13
courriel : [email protected]
Renseignements relatifs à l’Equipe :
Nom de l’Equipe d’Accueil : Physiopathologie des hormones PRL/GH : Approches transversales
Nom et prénom du responsable : Vincent Goffin
Qualité du responsable : DR2 Inserm
Téléphone :
01 72 60 63 68
Télécopie : 01 72 61 64 01
courriel : [email protected]
Renseignements relatifs au sujet de thèse :
Nom et prénom du Directeur de thèse (HDR) : Jacques-Emmanuel GUIDOTTI
Qualité : CR Inserm
Téléphone :
01 72 60 63 77
Télécopie : 01 72 61 64 01
courriel : [email protected]
Titre du sujet proposé :
(en français) Cellules progénitrices luminales prostatiques: de la physiologie au cancer
(en anglais) Prostatic luminal progenitor cells: from physiology to cancer
Département (cocher le département correspondant au sujet de thèse qui n’est pas obligatoirement le
vôtre) :
 Biologie Cellulaire et moléculaire, Physiologie et Physiopathologie
 Immunologie
 Développement Génétique Neurobiologie et Vieillissement
 Infectiologie, Microbiologie
Summary (5 lignes maximum):
We recently discovered a rare population of luminal progenitors in the mouse prostate. Based on their
androgen-independence these cells are candidate to participate in prostate cancer recurrence after
escape to anti-androgen therapy. We aim to determine their cell lineage origin, to understand the
molecular mechanisms that govern their proliferation, to assess their actual oncogenic potency and to
identify specific markers to establish their relevance in various contexts of mouse and human prostate
tumorigenesis.
Proposition de sujet de thèse à l’appui d’une demande de contrat doctoral 2015-2016
Nom, prénom du directeur de l'unité de recherche : Xavier Nassif
Numéro de l'unité de recherche (et établissement de rattachement) : Inserm U1151
Nom, prénom du responsable de l'équipe d'accueil (EAD) : Vincent Goffin
Nom, prénom du directeur de thèse : Jacques-Emmanuel Guidotti
Titre du sujet de thèse proposé : Cellules progénitrices luminales prostatiques : de la physiologie
au cancer
Citer 5 mots clés: progenitor cells, prostate, genetically-modified mouse, Stat5 signaling, cancer
Candidat pressenti :

OUI

NON
Contenu scientifique du programme de la thèse (en anglais)
The treatment of advanced prostate cancer involves hormone therapy, which targets androgens
whose role in tumor progression has been long acknowledged. Unfortunately, prostate cancer becomes
eventually resistant to these treatments ("hormone-resistance"), leading to bone metastasis and
ultimately patient death. It is thus essential to understand the cellular and molecular mechanisms that
are used by prostate tumors to continue to progress in the absence of androgenic stimuli. In this respect,
recent evidence suggests that stem/progenitor cells may play a role in tumor recurrence, based on the
fact that these cells are not dependent on (though responsive to) androgens.
We recently identified in wild type mice a small contingent of prostate cells exhibiting properties of
luminal progenitor cells. We showed that these cells survived castration, demonstrating their androgenindependence. Notably, we demonstrated that this progenitor contingent was amplified in transgenic
mice over-activating the prolactin / Stat5 signaling pathway in the luminal cell compartment (so-called
Pb-PRL mice). In addition to be a suitable tool to analyze these progenitor cells otherwise very rare,
these mice provide clues on the mechanisms and pathways that regulate these prostate progenitor cells.
The major aims of this project are to better characterize these newly identified progenitor cells in
physiological contexts, and to determine their potential role in cancer initiation/recurrence. Based on the
cell population-specific transcriptomes that we have generated, our first aim will be to identify progenitor
cell-specific markers allowing to track them in fixed prostate samples. Their identification in various
prostate cancer models should assess their relevance in prostate tumorigenesis. Based on the same
transcriptomic data, we will identify then challenge paracrine factors/signaling pathways regulating the
proliferation of this compartment using functional in vivo assays (e.g. treat mice with pathway inhibitors,
or breed with relevant genetically modified mice). We will determine the cellular origin of these luminal
progenitors using lineage tracing (breed Pb-PRL mice with lineage-specific ‘Cre-mice’). Their actual
progenitor properties will be ascertained (quantified) using various in vitro assays (e.g. prostasphere,
organoïds) and their tumor-initiating properties will be assessed using in vivo graft experiments. These
studies will be extended to human prostate diseases (healthy, hypertrophy, androgen-responsive and resistant cancer) in order to establish their potential prognostic and/or functional relevance regarding
disease progression.
Indiquez les cinq meilleures publications récentes de l’équipe :
Rouet V, Bogorad RL, Kayser C, Kessal K, Genestie C, Bardier A, Grattan DR, Kelder B, Kopchick JJ, Kelly PA, et
al. Local prolactin is a target to prevent expansion of basal/stem cells in prostate tumors. Proc Natl Acad Sci
U S A. 2010
Sackmann-Sala L, Chiche A, Mosquera-Garrote N, Boutillon F, Cordier C, Pourmir I, Pascual-Mathey L, Kessal K,
Pigat N, Camparo P, et al. Prolactin-Induced Prostate Tumorigenesis Links Sustained Stat5 Signaling with the
Amplification of Basal/Stem Cells and Emergence of Putative Luminal Progenitors. Am J Pathol. 2014.
Sackmann-Sala L, Guidotti JE, and Goffin V. Minireview: Prolactin regulation of adult stem cells. Mol Endocrinol.
2015.
Bernichtein S, Pigat N, Camparo P, Latil A, Viltard M, Friedlander G, and Goffin V. Anti-inflammatory properties of
Lipidosterolic extract of Serenoa repens (Permixon®) in a mouse model of prostate hyperplasia. Prostate.
2015.
Bernichtein S, Pigat N, Capiod T, Boutillon F, Verkarre V, Camparo P, Viltard M, Mejean A, Oudard S, Souberbielle
JC, et al. High milk consumption does not affect prostate tumor progression in two mouse models of benign
and neoplastic lesions. PLoS ONE. 2015.