ecole doctorale « medicament - L`Institut de Formation Doctorale

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Proposition de sujet de thèse à l’appui d’une demande de contrat doctoral 2017-2018
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 : [e-mail]
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 : [e-mail]
Renseignements relatifs au sujet de thèse :
Nom et prénom du Directeur de thèse (HDR) : Jacques-Emmanuel GUIDOTTI
Qualité : CR1 Inserm
Téléphone : 01 72 60 63 77 Télécopie : 01 72 61 64 01
courriel : [e-mail]
Titre du sujet proposé :
(En français) Role des progéniteurs luminaux androgéno-indépendants dans la progression du
cancer prostatique
(En anglais) Role of castration-resistant luminal progenitors in prostate cancer relapse
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):
The current therapeutic challenge in prostate cancer management is to identify the mechanisms driving
resistance to androgen-deprivation therapy. In this project, we will challenge the role in this process of a
recently-discovered population of luminal progenitors that exhibit stem-like and androgen-independence
properties. We will investigate the molecular bases of their resistance to androgen deprivation, the
factors/pathways promoting their proliferation, and their tumorigenic potency in castrated mice.

Proposition de sujet de thèse à l’appui d’une demande de contrat doctoral 2017-2018
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 : Prostatic luminal progenitor cells: from physiology to cancer
Citer 5 mots clés: prostate cancer, resistance to treatment, stem/progenitor cells, androgen
signaling, proliferation
Candidat pressenti :  OUI  NON
Contenu scientifique du programme de la thèse (en anglais)
Invasive/metastatic prostate cancer is a lethal disease. Although these cancers initially regress under
anti-androgen therapy, they eventually develop resistance to treatment, leading to bone metastasis and
ultimately patient death. The current therapeutic challenge is to identify the mechanisms that are used by
(some) prostate cancer cells to survive/proliferate in the absence of androgens (castration tolerance). In
this respect we recently identified in the mouse a very rare population of prostate luminal progenitor cells
(representing <10% of epithelial cells) that exhibit stem-like properties and survive castration. Strikingly,
these cells are predominant (>80% of epithelial cells) in a model of aggressive prostate cancer driven by
the loss of the tumor suppressor PTEN, which supports their role in the progression of castration-
resistant prostate cancer. Comparative transcriptomic analysis of the various prostate epithelial cell
types showed that these luminal progenitors exhibit i) a specific gene signature, and ii) intrinsically low
androgen signaling, which likely explains their resistance to androgen deprivation. Based on this novel
data, we propose to investigate the mechanisms by which these luminal progenitors may circumvent
androgen deprivation and drive prostate cancer recurrence.
1. The luminal progenitor gene signature harbors candidate paracrine factors/signaling pathways
suspected to promote their proliferation. Using various in vitro assays of primary culture of prostate
progenitor cell (prostaspheres, organoïds), we will challenge these candidate pathways using
pharmacological and/or genetic approaches (as available).
2. We identified co-activators/co-repressors of androgen signaling that may regulate the androgen
sensitivity in these cells. We will determine their impact on resistance to androgen deprivation by
genetic manipulation of their expression level in primary cell cultures (see above) in various androgen
contexts. In vivo experiments aimed to confirm relevant in vitro results will be conducted as possible.
3. We have demonstrated the tumor-initiating properties of PTEN-deficient luminal progenitor cells when
subcutaneously engrafted into immunodeficient mice. By castrating the host mice at various
timepoints after cell engraftment, the ability of luminal progenitors to (re-)generate tumors in the
absence of androgen will be assessed. A time-course analysis of luminal progenitor prevalence after
castration of PTEN-deficient mice will provide complementary data in a model of endogenous tumor
relapse.
This project will provide mechanistic and functional insight on the castration-tolerance of these luminal
progenitors in a cancer context. Together with an ongoing study investigating their prevalence in human
prostate cancer (cohort analysis), the results obtained should open new therapeutic and/or prognosis
opportunities for the clinical management of advanced (castration-resistant) prostate cancer.
Indiquez les cinq meilleures publications récentes de l’équipe :
Sackmann-Sala L, […] Guidotti J.-E., Goffin, V. A rare castration-resistant progenitor cell population is highly
enriched in Pten-null prostate tumors. J Pathol. in favorable revision.
Sackmann-Sala L, Guidotti J.-E., and Goffin V. Minireview: Prolactin regulation of adult stem cells. Mol
Endocrinol. 2015.
Sackmann-Sala, L., A. […] V. Goffin. "Human and murine prostate basal/stem cells are not direct targets of
prolactin." Gen. Comp Endocrinol 2015
Sackmann-Sala L, […] Goffin, V. 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.

Rouet V, […] Goffin, V. Local prolactin is a target to prevent expansion of basal/stem cells in prostate tumors. Proc
Natl Acad Sci U S A. 2010