5-Carboxylcytosine is localized to euchromatic regions in the nuclei of follicular cells in axolotl ovary

5-Methylcytosine (5-mC) is an epigenetic modification associated with gene repression. Recent studies demonstrated that 5-mC can be enzymatically oxidised into 5-hydroxymethylcytosine and further into 5-formylcytosine (5-fC) and 5-carboxylcytsine (5-caC). 5-caC has been found in embryonic stem cells and in mouse pre-implantation embryos but no detectable levels of this modification have been reported for somatic tissues to date. Whereas it has been suggested that 5-caC can serve as an intermediate in the process of active demethylation, the function of this form of modified cytosine remains obscure. Here we show that 5-caC is immunochemically detectable in somatic cells of axolotl ovary. We demonstrate that both 5-hmC and 5-caC are localized to the euchromatin in the nuclei of axolotl follicular cells with similar patterns of spatial distribution. Our results suggest that 5-carboxylcytosine may play a distinct functional role in certain biological contexts

Rôle des récepteurs aux oxystérols LXRs (Liver X Receptors) dans la dissémination métastatique du cancer de la prostate

Clinical management of prostate cancer is complex. The identification of elements and genetic alterations involved in disease progression is therefore crucial. Metabolic alterations represent key modifications during tumor cell growth. Among these modifications, cholesterol metabolism increase is frequently observed in various tumor pathologies, including prostate cancer. Related, epidemiological studies associate cholesterol enrichment with an increase of disease incidence, progression and aggressiveness. LXRs (Liver X Receptors) belong to the nuclear receptors superfamily and represent major sensors and regulators of cholesterol homeostasis. Recent studies have demonstrated their antiproliferative and pro-apoptotic potential in various prostate cancer cell lines. In link, this thesis work demonstrate endogenous and constitutive activation of LXRs in a murine model of PTEN-dependent prostate adenocarcinoma in response to an increase of intra-prostatic cholesterol, the major source of oxysterol ligands. The additional invalidation of LXRs in this context leads to a significant increase of tumor growth and metastatic dissemination, notably explained by a TGFβ pathway deregulation, concomitant with epithelial-mesenchymal transition process increase. All of these results define LXRs as promising therapeutic targets.La prise en charge clinique du cancer de la prostate est complexe. L’identification des éléments et altérations génétiques impliqués dans la progression de la maladie est donc capitale. Les altérations métaboliques représentent des changements clés vis-à-vis de la croissance de la cellule tumorale. Parmi ces modifications, l’augmentation du métabolisme du cholestérol est fréquemment observée au sein de différentes pathologies tumorales, dont le cancer de la prostate. En lien, des études épidémiologiques associent l’enrichissement du cholestérol avec une augmentation de l’incidence, la progression et l’agressivité de la maladie. Les récepteurs nucléaires aux oxystérols LXRs (Liver X Receptors) constituent des régulateurs majeurs de l’homéostasie du cholestérol, et différents travaux récents mettent en évidence leur potentiel anti-prolifératif et pro-apoptotique dans différentes lignées cellulaires du cancer de la prostate. En association ces travaux de thèse démontrent, dans un modèle murin d’adénocarcinome prostatique PTEN-dépendant, une activation endogène et constitutive des LXRs en réponse à une augmentation du taux de cholestérol intra-prostatique, principale source des ligands oxystérols. L’invalidation additionnelle des LXRs dans ce contexte conduit à une augmentation importante de la croissance tumorale et à la dissémination métastatique, notamment expliquée par une dérégulation de la voie du TGFβ et de la transition épithélio-mésenchymateuse. L'ensemble de ces résultats place les LXRs comme des cibles thérapeutiques prometteuses

LXRs (Liver X Receptors) involvement during prostate cancer metastatic dissemination

La prise en charge clinique du cancer de la prostate est complexe. L’identification des éléments et altérations génétiques impliqués dans la progression de la maladie est donc capitale. Les altérations métaboliques représentent des changements clés vis-à-vis de la croissance de la cellule tumorale. Parmi ces modifications, l’augmentation du métabolisme du cholestérol est fréquemment observée au sein de différentes pathologies tumorales, dont le cancer de la prostate. En lien, des études épidémiologiques associent l’enrichissement du cholestérol avec une augmentation de l’incidence, la progression et l’agressivité de la maladie. Les récepteurs nucléaires aux oxystérols LXRs (Liver X Receptors) constituent des régulateurs majeurs de l’homéostasie du cholestérol, et différents travaux récents mettent en évidence leur potentiel anti-prolifératif et pro-apoptotique dans différentes lignées cellulaires du cancer de la prostate. En association ces travaux de thèse démontrent, dans un modèle murin d’adénocarcinome prostatique PTEN-dépendant, une activation endogène et constitutive des LXRs en réponse à une augmentation du taux de cholestérol intra-prostatique, principale source des ligands oxystérols. L’invalidation additionnelle des LXRs dans ce contexte conduit à une augmentation importante de la croissance tumorale et à la dissémination métastatique, notamment expliquée par une dérégulation de la voie du TGFβ et de la transition épithélio-mésenchymateuse. L'ensemble de ces résultats place les LXRs comme des cibles thérapeutiques prometteuses.Clinical management of prostate cancer is complex. The identification of elements and genetic alterations involved in disease progression is therefore crucial. Metabolic alterations represent key modifications during tumor cell growth. Among these modifications, cholesterol metabolism increase is frequently observed in various tumor pathologies, including prostate cancer. Related, epidemiological studies associate cholesterol enrichment with an increase of disease incidence, progression and aggressiveness. LXRs (Liver X Receptors) belong to the nuclear receptors superfamily and represent major sensors and regulators of cholesterol homeostasis. Recent studies have demonstrated their antiproliferative and pro-apoptotic potential in various prostate cancer cell lines. In link, this thesis work demonstrate endogenous and constitutive activation of LXRs in a murine model of PTEN-dependent prostate adenocarcinoma in response to an increase of intra-prostatic cholesterol, the major source of oxysterol ligands. The additional invalidation of LXRs in this context leads to a significant increase of tumor growth and metastatic dissemination, notably explained by a TGFβ pathway deregulation, concomitant with epithelial-mesenchymal transition process increase. All of these results define LXRs as promising therapeutic targets

Dans le labyrinthe de la pensée

Ce volume propose une relecture du Qu’est-ce que la philosophie?, ultime opus (1991) écrit à quatre mains par Gilles Deleuze et Félix Guattari. Il veut donner accès à ce texte difficile en montrant comment les concepts qui y sont définis permettent de penser plus avant, entre autres la composition musicale et le geste même de prendre pour objet l’acte de philosopher. Il invite encore à confronter la pensée des deux philosophes à d’autres réflexions, amies ou ennemies. Mais il montre encore que, loin d’être une météorite, l’œuvre s’inscrit, jusque dans sa créativité la plus débridée, dans la tradition de la métaphysique occidentale. A ce titre, le volume n’est donc pas un simple essai de doxographie. Il se veut une tentative de penser dans le sillage ouvert par l’inventivité philosophique de Gilles Deleuze et Félix Guattari, en même temps qu’une invitation à déplier la créativité de sa propre pensée au contact d’une œuvre dont la fécondité est encore à venir

Oxysterol receptors and their therapeutic applications in cancer conditions

International audienceINTRODUCTION: Oxysterols are implicated in various cellular processes. Among their target proteins, liver X receptors (LXRs) alpha and beta modulate the cell cycle in a large range of cancer cell lines. Besides their role as cholesterol sensors, LXRs are also involved in the proliferation/apoptosis balance regulation in various types of cancers. AREAS COVERED: This review covers oxysterols and derivatives of cholesterol as well as synthetic or natural ligands (agonist/antagonist) of LXRs. Most tumor cell lines are sensitive to LXR activation. Indeed various cancers are concerned such as prostate, breast, glioblastoma, colorectal, and ovary tumors, and leukemia. EXPERT OPINION: Developing the use of LXR ligands in human health, especially in the field of cancer, represents a novel and promising strategy. Despite a wide spectrum of applications, numerous adverse effects of LXR activation need to be solved before genuine clinical trials in humans. Future directions will be based on the engineering of selective LXRs modulators (SLiMs) as already done for nuclear steroid receptors

Retraction: Liver X receptors constrain tumor development and metastasis dissemination in PTEN-deficient prostate cancer (Nature Communications DOI: 10.1038/s41467-017-00508-5)

In this Article, we reported that liver X receptors constrain metastatic development of prostate cancer in Pten-null mice. However, following institutional investigations by Université Clermont Auvergne, it has come to our attention that much of the data reported in the paper were a result of manipulation or fabrication. Specifically, differences in protein expression in western blots presented in Fig. 1e, 3b, g, i, m, and 6b, and Supplementary Figures 2d, 6d, 6h, 7h, 8c, 8d, and 14 were generated by unequal loading of samples. In qPCR experiments presented in Figs. 1f, 3f, 4g, 5h, and 6a, d and Supplementary Figures 2c, 5d, 6g, 8d, 11a-c, and 12b, differences in expression level were manipulated through adjustment of cycle numbers, selection of samples, and data fabrication. Differences in immunostaining in Figs. 2g, k and 7e were obtained by selection of images or manipulation of exposure levels. Observed differences in relative luminescence units in Figs. 3m, 4e, and Supplementary Figures 6f, 7a, 7b, 10, and 11f were due to experiment selection. In light of these findings, we have no confidence in the accuracy of the reported data and the conclusions of the paper. We therefore wish to retract the paper. We deeply regret these circumstances and apologize to the scientific community

RETRACTED ARTICLE: Liver X receptors constrain tumor development and metastasis dissemination in PTEN-deficient prostate cancer

Treatment of prostate cancer, especially in its advanced stage, is still challenging; therefore, strategies to prevent metastatic dissemination are of great interest. Here the authors reveal a crucial role for liver X receptors in suppressing prostate carcinogenesis and metastatic progression in PTEN-null tumors