Publications de l'équipe - UMR3244 - Dynamique de l'information génétique - Centre de Recherche Institut Curie
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
Publications de l’équipe
UMR3244 – Dynamique de l’information génétique
Année de publication : 2019
Katrin Möller, Sara Sigurbjornsdottir, Asgeir O Arnthorsson, Vivian Pogenberg, Ramile Dilshat,
Valerie Fock, Solveig H Brynjolfsdottir, Christian Bindesboll, Margret Bessadottir, Helga M
Ogmundsdottir, Anne Simonsen, Lionel Larue, Matthias Wilmanns, Vesteinn Thorsson, Eirikur
Steingrimsson, Margret H Ogmundsdottir (2019 Feb 2)
MITF has a central role in regulating starvation-induced autophagy in
melanoma.
Scientific reports : 1055 : DOI : 10.1038/s41598-018-37522-6
Résumé
The MITF transcription factor is a master regulator of melanocyte development and a critical
factor in melanomagenesis. The related transcription factors TFEB and TFE3 regulate
lysosomal activity and autophagy processes known to be important in melanoma. Here we
show that MITF binds the CLEAR-box element in the promoters of lysosomal and
autophagosomal genes in melanocytes and melanoma cells. The crystal structure of MITF
bound to the CLEAR-box reveals how the palindromic nature of this motif induces symmetric
MITF homodimer binding. In metastatic melanoma tumors and cell lines, MITF positively
correlates with the expression of lysosomal and autophagosomal genes, which, interestingly,
are different from the lysosomal and autophagosomal genes correlated with TFEB and TFE3.
Depletion of MITF in melanoma cells and melanocytes attenuates the response to starvation-
induced autophagy, whereas the overexpression of MITF in melanoma cells increases the
number of autophagosomes but is not sufficient to induce autophagic flux. Our results
suggest that MITF and the related factors TFEB and TFE3 have separate roles in regulating a
starvation-induced autophagy response in melanoma. Understanding the normal and
pathophysiological roles of MITF and related transcription factors may provide important
clinical insights into melanoma therapy.
Konrad Gronke, Pedro P Hernández, Jakob Zimmermann, Christoph S N Klose, Michael Kofoed-
Branzk, Fabian Guendel, Mario Witkowski, Caroline Tizian, Lukas Amann, Fabian Schumacher,
Hansruedi Glatt, Antigoni Triantafyllopoulou, Andreas Diefenbach (2019 Feb 1)
Interleukin-22 protects intestinal stem cells against genotoxic stress.
Nature : 249-253 : DOI : 10.1038/s41586-019-0899-7
Résumé
Environmental genotoxic factors pose a challenge to the genomic integrity of epithelial cells
at barrier surfaces that separate host organisms from the environment. They can induce
mutations that, if they occur in epithelial stem cells, contribute to malignant transformation
and cancer development. Genome integrity in epithelial stem cells is maintained by an
evolutionarily conserved cellular response pathway, the DNA damage response (DDR). The
DDR culminates in either transient cell-cycle arrest and DNA repair or elimination of
damaged cells by apoptosis. Here we show that the cytokine interleukin-22 (IL-22), produced
INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 1Publications de l’équipe
UMR3244 – Dynamique de l’information génétique
by group 3 innate lymphoid cells (ILC3) and γδ T cells, is an important regulator of the DDR
machinery in intestinal epithelial stem cells. Using a new mouse model that enables sporadic
inactivation of the IL-22 receptor in colon epithelial stem cells, we demonstrate that IL-22 is
required for effective initiation of the DDR following DNA damage. Stem cells deprived of
IL-22 signals and exposed to carcinogens escaped DDR-controlled apoptosis, contained more
mutations and were more likely to give rise to colon cancer. We identified metabolites of
glucosinolates, a group of phytochemicals contained in cruciferous vegetables, to be a
widespread source of genotoxic stress in intestinal epithelial cells. These metabolites are
ligands of the aryl hydrocarbon receptor (AhR), and AhR-mediated signalling in ILC3 and γδ T
cells controlled their production of IL-22. Mice fed with diets depleted of glucosinolates
produced only very low levels of IL-22 and, consequently, the DDR in epithelial cells of mice
on a glucosinolate-free diet was impaired. This work identifies a homeostatic network
protecting stem cells against challenge to their genome integrity by AhR-mediated ‘sensing’
of genotoxic compounds from the diet. AhR signalling, in turn, ensures on-demand
production of IL-22 by innate lymphocytes directly regulating components of the DDR in
epithelial stem cells.
Nathalie Fretellier, Agnès Granottier, Marlène Rasschaert, Anne-Laure Grindel, Fannie
Baudimont, Philippe Robert, Jean-Marc Idée, Claire Corot (2019 Feb 1)
Does Age Interfere With Gadolinium Toxicity and Presence in Brain and Bone
Tissues?: A Comparative Gadoterate Versus Gadodiamide Study in Juvenile and
Adult Rats.
Investigative radiology : 54 : 61-71 : DOI : 10.1097/RLI.0000000000000517
Résumé
Objectives
The main objective of the study was to assess the effect of age on target tissue total
gadolinium (Gd) retention after repeated administration of gadodiamide (linear) or
gadoterate (macrocyclic) Gd-based contrast agent (GBCA) in rats. The secondary objective
was to assess the potential developmental and long-term consequences of GBCA
administration during neonatal and juvenile periods.
Materials and Methods
A total of 20 equivalent human clinical doses (cumulated dose, 12 mmol Gd/kg) of either
gadoterate or gadodiamide were administered concurrently by the intravenous route to
healthy adult and juvenile rats. Saline was administered to juvenile rats forming the control
group. In juvenile rats, the doses were administered from postnatal day 12, that is, once the
blood-brain barrier is functional as in humans after birth. The tests were conducted on 5
juvenile rats per sex and per group and on 3 adult animals per sex and per group. T1-
weighted magnetic resonance imaging of the cerebellum was performed at 4.7 T during both
the treatment and treatment-free periods. Behavioral tests were performed in juvenile rats.
Rats were euthanatized at 11 to 12 weeks (ie, approximately 3 months) after the last
INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 2Publications de l’équipe
UMR3244 – Dynamique de l’information génétique
administration. Total Gd concentrations were measured in plasma, skin, bone, and brain by
inductively coupled plasma mass spectrometry. Cerebellum samples from the juvenile rats
were characterized by histopathological examination (including immunohistochemistry for
glial fibrillary acidic protein or GFAP, and CD68). Lipofuscin pigments were also studied by
fluorescence microscopy. All tests were performed blindly on randomized animals.
Results
Transient skin lesions were observed in juvenile rats (5/5 females and 2/4 males) and not in
adult rats having received gadodiamide. Persisting (up to completion of the study) T1
hyperintensity in the deep cerebellar nuclei (DCNs) was observed only in gadodiamide-
treated rats. Quantitatively, a slightly higher progressive increase in the DCN/brain stem
ratio was observed in adult rats compared with juvenile rats, whereas no difference was
noted visually. In all tissues, total Gd concentrations were higher (10- to 30-fold higher) in
the gadodiamide-treated groups than in the gadoterate groups. No age-related differences
were observed except in bone marrow where total Gd concentrations in gadodiamide-treated
juvenile rats were higher than those measured in adults and similar to those measured in
cortical bone tissue. No significant treatment-related effects were observed in
histopathological findings or in development, behavior, and biochemistry parameters.
However, in the elevated plus maze test, a trend toward an anxiogenic effect was observed
in the gadodiamide group compared with other groups (nonsignificant). Moreover, in the
balance beam test, a high number of trials were excluded in the gadodiamide group because
rats (mainly males) did not completely cross the beam, which may also reflect an anxiogenic
effect.
Conclusions
No T1 hyperintensity was observed in the DCN after administration of the macrocyclic GBCA
gadoterate regardless of age as opposed to administration of the linear GBCA gadodiamide.
Repeated administration of gadodiamide in neonatal and juvenile rats resulted in similar
total Gd retention in the skin, brain, and bone to that in adult rats with sex having no effect,
whereas Gd distribution in bone marrow was influenced by age. Further studies are required
to assess the form of the retained Gd and to investigate the potential risks associated with
Gd retention in bone marrow in juvenile animals treated with gadodiamide. Regardless of
age, total Gd concentration in the brain and bone was 10- to 30-fold higher after
administration of gadodiamide compared with gadoterate.
Larissa Mourao, Guillaume Jacquemin, Mathilde Huyghe, Wojciech J Nawrocki, Naoual Menssouri,
Nicolas Servant, Silvia Fre (2019 Jan 31)
Lineage tracing of Notch1-expressing cells in intestinal tumours reveals a
distinct population of cancer stem cells.
Scientific reports : 888 : DOI : 10.1038/s41598-018-37301-3
Résumé
INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 3Publications de l’équipe
UMR3244 – Dynamique de l’information génétique
Colon tumours are hierarchically organized and contain multipotent self-renewing cells,
called Cancer Stem Cells (CSCs). We have previously shown that the Notch1 receptor is
expressed in Intestinal Stem Cells (ISCs); given the critical role played by Notch signalling in
promoting intestinal tumourigenesis, we explored Notch1 expression in tumours. Combining
lineage tracing in two tumour models with transcriptomic analyses, we found that Notch1+
tumour cells are undifferentiated, proliferative and capable of indefinite self-renewal and of
generating a heterogeneous clonal progeny. Molecularly, the transcriptional signature of
Notch1+ tumour cells highly correlates with ISCs, suggestive of their origin from normal
crypt cells. Surprisingly, Notch1+ expression labels a subset of CSCs that shows reduced
levels of Lgr5, a reported CSCs marker. The existence of distinct stem cell populations within
intestinal tumours highlights the necessity of better understanding their hierarchy and
behaviour, to identify the correct cellular targets for therapy.
Chia-Hsiang Chang, Marco Zanini, Hamasseh Shirvani, Jia-Shing Cheng, Hua Yu, Chih-Hsin Feng,
Audrey L Mercier, Shiue-Yu Hung, Antoine Forget, Chun-Hung Wang, Sara Maria Cigna, I-Ling Lu,
Wei-Yi Chen, Sophie Leboucher, Won-Jing Wang, Martial Ruat, Nathalie Spassky, Jin-Wu Tsai,
Olivier Ayrault (2019 Jan 30)
Atoh1 Controls Primary Cilia Formation to Allow for SHH-Triggered Granule
Neuron Progenitor Proliferation.
Developmental cell : 184-199.e5 : DOI : S1534-5807(18)31085-2
Résumé
During cerebellar development, granule neuron progenitors (GNPs) proliferate by
transducing Sonic Hedgehog (SHH) signaling via the primary cilium. Precise regulation of
ciliogenesis, thus, ensures proper GNP pool expansion. Here, we report that Atoh1, a
transcription factor required for GNPs formation, controls the presence of primary cilia,
maintaining GNPs responsiveness to SHH. Loss of primary cilia abolishes the ability of Atoh1
to keep GNPs in a proliferative state. Mechanistically, Atoh1 promotes ciliogenesis by
transcriptionally regulating Cep131, which facilitates centriolar satellite (CS) clustering to
the basal body. Importantly, ectopic expression of Cep131 counteracts the effects of Atoh1
loss in GNPs by restoring proper localization of CS and ciliogenesis. This Atoh1-CS-primary
cilium-SHH pro-proliferative pathway is also conserved in SHH-type medulloblastoma, a
pediatric brain tumor arising from the GNPs. Together, our data reveal how Atoh1 modulates
the primary cilium to regulate GNPs development.
Maria Duda, Natalie J Kirkland, Nargess Khalilgharibi, Melda Tozluoglu, Alice C Yuen, Nicolas
Carpi, Anna Bove, Matthieu Piel, Guillaume Charras, Buzz Baum, Yanlan Mao (2019 Jan 30)
Polarization of Myosin II Refines Tissue Material Properties to Buffer Mechanical
Stress.
Developmental cell : 245-260.e7 : DOI : S1534-5807(18)31088-8
Résumé
As tissues develop, they are subjected to a variety of mechanical forces. Some of these
INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 4Publications de l’équipe
UMR3244 – Dynamique de l’information génétique
forces are instrumental in the development of tissues, while others can result in tissue
damage. Despite our extensive understanding of force-guided morphogenesis, we have only
a limited understanding of how tissues prevent further morphogenesis once the shape is
determined after development. Here, through the development of a tissue-stretching device,
we uncover a mechanosensitive pathway that regulates tissue responses to mechanical
stress through the polarization of actomyosin across the tissue. We show that stretch
induces the formation of linear multicellular actomyosin cables, which depend on
Diaphanous for their nucleation. These stiffen the epithelium, limiting further changes in
shape, and prevent fractures from propagating across the tissue. Overall, this mechanism of
force-induced changes in tissue mechanical properties provides a general model of force
buffering that serves to preserve the shape of tissues under conditions of mechanical stress.
Delphine Naud-Martin, Corinne Landras-Guetta, Daniela Verga, Deepanjan Ghosh, Sylvain
Achelle, Florence Mahuteau-Betzer, Sophie Bombard, Marie-Paule Teulade-Fichou (2019 Jan 26)
Selectivity of Terpyridine Platinum Anticancer Drugs for G-quadruplex DNA.
Molecules (Basel, Switzerland) : 24 : 404 : DOI : 10.3390/molecules24030404
Résumé
Guanine-rich DNA can form four-stranded structures called G-quadruplexes (G4s) that can
regulate many biological processes. Metal complexes have shown high affinity and
selectivity toward the quadruplex structure. Here, we report the comparison of a panel of
platinum (II) complexes for quadruplex DNA selective recognition by exploring the aromatic
core around terpyridine derivatives. Their affinity and selectivity towards G4 structures of
various topologies have been evaluated by FRET-melting (Fluorescence Resonance Energy
Transfert-melting) and Fluorescent Intercalator Displacement (FID) assays, the latter
performed by using three different fluorescent probes (Thiazole Orange (TO), TO-PRO-3, and
PhenDV). Their ability to bind covalently to the c-myc G4 structure in vitro and their
cytotoxicity potential in two ovarian cancerous cell lines were established. Our results show
that the aromatic surface of the metallic ligands governs, in vitro, their affinity, their
selectivity for the G4 over the duplex structures, and platination efficiency. However, the
structural modifications do not allow significant discrimination among the different G4
topologies. Moreover, all compounds were tested on ovarian cancer cell lines and normal cell
lines and were all able to overcome cisplatin resistance highlighting their interest as new
anticancer drugs.
Pietro Mancuso, Rossella Tricarico, Vikram Bhattacharjee, Laura Cosentino, Yuwaraj Kadariya,
Jaroslav Jelinek, Emmanuelle Nicolas, Margret Einarson, Neil Beeharry, Karthik Devarajan,
Richard A Katz, Dorjbal G Dorjsuren, Hongmao Sun, Anton Simeonov, Antonio Giordano, Joseph R
Testa, Guillaume Davidson, Irwin Davidson, Lionel Larue, Robert W Sobol, Timothy J Yen, Alfonso
Bellacosa (2019 Jan 25)
Thymine DNA glycosylase as a novel target for melanoma.
Oncogene : DOI : 10.1038/s41388-018-0640-2
INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 5Publications de l’équipe
UMR3244 – Dynamique de l’information génétique
Résumé
Melanoma is an aggressive neoplasm with increasing incidence that is classified by the NCI
as a recalcitrant cancer, i.e., a cancer with poor prognosis, lacking progress in diagnosis and
treatment. In addition to conventional therapy, melanoma treatment is currently based on
targeting the BRAF/MEK/ERK signaling pathway and immune checkpoints. As drug resistance
remains a major obstacle to treatment success, advanced therapeutic approaches based on
novel targets are still urgently needed. We reasoned that the base excision repair enzyme
thymine DNA glycosylase (TDG) could be such a target for its dual role in safeguarding the
genome and the epigenome, by performing the last of the multiple steps in DNA
demethylation. Here we show that TDG knockdown in melanoma cell lines causes cell cycle
arrest, senescence, and death by mitotic alterations; alters the transcriptome and
methylome; and impairs xenograft tumor formation. Importantly, untransformed
melanocytes are minimally affected by TDG knockdown, and adult mice with conditional
knockout of Tdg are viable. Candidate TDG inhibitors, identified through a high-throughput
fluorescence-based screen, reduced viability and clonogenic capacity of melanoma cell lines
and increased cellular levels of 5-carboxylcytosine, the last intermediate in DNA
demethylation, indicating successful on-target activity. These findings suggest that TDG may
provide critical functions specific to cancer cells that make it a highly suitable anti-melanoma
drug target. By potentially disrupting both DNA repair and the epigenetic state, targeting
TDG may represent a completely new approach to melanoma therapy.
CAMPAGNE Antoine, LEE Ming-Kang, ZIELINSKI Dina, MICHAUD Audrey, LE CORRE Stéphanie,
DINGLI Florent, CHEN Hong, SHAHIDIAN Lara Z, SERVANT Nicolas, LOEW Damarys, PASMANT
Eric, PISTEL-VINAY Sophie, WASSEF Michel, MARGUERON Raphaël (2019 Jan 21)
BAP1 complex promotes transcription by opposing PRC1-mediated H2A
ubiquitylation
Nature Communications : DOI : 10.1038/s41467-018-08255-x
Résumé
In Drosophila, a complex consisting of Calypso and ASX catalyzes H2A deubiquitination and
has been reported to act as part of the Polycomb machinery in transcriptional silencing. The
mammalian homologs of these proteins (BAP1 and ASXL1/2/3, respectively), are frequently
mutated in various cancer types, yet their precise functions remain unclear. Using an
integrative approach based on isogenic cell lines generated with CRISPR/Cas9, we uncover
an unanticipated role for BAP1 in gene activation. This function requires the assembly of an
enzymatically active BAP1-associated core complex (BAP1.com) containing one of the
redundant ASXL proteins. We investigate the mechanism underlying BAP1.com-mediated
transcriptional regulation and show that it does not participate in Polycomb-mediated
silencing. Instead, our results establish that the function of BAP1.com is to safeguard
transcriptionally active genes against silencing by the Polycomb Repressive Complex 1.
M Schmidt-Cernohorska, I Zhernov, E Steib, M Le Guennec, R Achek, S Borgers, D Demurtas, L
INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 6Publications de l’équipe
UMR3244 – Dynamique de l’information génétique
Mouawad, Z Lansky, V Hamel, P Guichard (2019 Jan 19)
Flagellar microtubule doublet assembly in vitro reveals a regulatory role of
tubulin C-terminal tails.
Science (New York, N.Y.) : 363 : 285-288 : DOI : 10.1126/science.aav2567
Résumé
Microtubule doublets (MTDs), consisting of an incomplete B-microtubule at the surface of a
complete A-microtubule, provide a structural scaffold mediating intraflagellar transport and
ciliary beating. Despite the fundamental role of MTDs, the molecular mechanism governing
their formation is unknown. We used a cell-free assay to demonstrate a crucial inhibitory role
of the carboxyl-terminal (C-terminal) tail of tubulin in MTD assembly. Removal of the C-
terminal tail of an assembled A-microtubule allowed for the nucleation of a B-microtubule on
its surface. C-terminal tails of only one A-microtubule protofilament inhibited this side-to-
surface tubulin interaction, which would be overcome in vivo with binding protein partners.
The dynamics of B-microtubule nucleation and its distinctive isotropic elongation was
elucidated by using live imaging. Thus, inherent interaction properties of tubulin provide a
structural basis driving flagellar MTD assembly.
Pamela Caudana, Nicolas Gonzalo Núñez, Philippe De La Rochere, Anaïs Pinto, Jordan Denizeau,
Ruby Alonso, Leticia Laura Niborski, Olivier Lantz, Christine Sedlik, Eliane Piaggio (2019 Jan 18)
IL2/Anti-IL2 Complex Combined with CTLA-4, But Not PD-1, Blockade Rescues
Antitumor NK Cell Function by Regulatory T-cell Modulation.
Cancer immunology research : 443-457 : DOI : 10.1158/2326-6066.CIR-18-0697
Résumé
High-dose IL2 immunotherapy can induce long-lasting cancer regression but is toxic and
insufficiently efficacious. Improvements are obtained with IL2/anti-IL2 complexes (IL2Cx),
which redirect IL2 action to CD8 T and natural killer (NK) cells. Here, we evaluated the
efficacy of combining IL2Cx with blockade of inhibitory immune pathways. In an
autochthonous lung adenocarcinoma model, we show that the IL2Cx/anti-PD-1 combination
increases CD8 T-cell infiltration of the lung and controls tumor growth. In the B16-OVA
model, which is resistant to checkpoint inhibition, combination of IL2Cx with PD-1 or CTLA-4
pathway blockade reverses that resistance. Both combinations work by reinvigorating
exhausted intratumoral CD8 T cells and by increasing the breadth of tumor-specific T-cell
responses. However, only the IL2Cx/anti-CTLA-4 combination is able to rescue NK cell
antitumor function by modulating intratumoral regulatory T cells. Overall, association of
IL2Cx with PD-1 or CTLA-4 pathway blockade acts by different cellular mechanisms, paving
the way for the rational design of combinatorial antitumor therapies.
Viviana Barra, Glennis A Logsdon, Andrea Scelfo, Sebastian Hoffmann, Solène Hervé, Aaron
Aslanian, Yael Nechemia-Arbely, Don W Cleveland, Ben E Black, Daniele Fachinetti (2019 Jan 13)
INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 7Publications de l’équipe
UMR3244 – Dynamique de l’information génétique
Phosphorylation of CENP-A on serine 7 does not control centromere function.
Nature communications : 175 : DOI : 10.1038/s41467-018-08073-1
Résumé
CENP-A is the histone H3 variant necessary to specify the location of all eukaryotic
centromeres via its CENP-A targeting domain and either one of its terminal regions. In
humans, several post-translational modifications occur on CENP-A, but their role in
centromere function remains controversial. One of these modifications of CENP-A,
phosphorylation on serine 7, has been proposed to control centromere assembly and
function. Here, using gene targeting at both endogenous CENP-A alleles and gene
replacement in human cells, we demonstrate that a CENP-A variant that cannot be
phosphorylated at serine 7 maintains correct CENP-C recruitment, faithful chromosome
segregation and long-term cell viability. Thus, we conclude that phosphorylation of CENP-A
on serine 7 is dispensable to maintain correct centromere dynamics and function.
Hannah L Klein, Giedrė Bačinskaja, Jun Che, Anais Cheblal, Rajula Elango, Anastasiya Epshtein,
Devon M Fitzgerald, Belén Gómez-González, Sharik R Khan, Sandeep Kumar, Bryan A Leland, Léa
Marie, Qian Mei, Judith Miné-Hattab, Alicja Piotrowska, Erica J Polleys, Christopher D Putnam,
Elina A Radchenko, Anissia Ait Saada, Cynthia J Sakofsky, Eun Yong Shim, Mathew Stracy, Jun
Xia, Zhenxin Yan, Yi Yin, Andrés Aguilera, Juan Lucas Argueso, Catherine H Freudenreich, Susan
M Gasser, Dmitry A Gordenin, James E Haber, Grzegorz Ira, Sue Jinks-Robertson, Megan C King,
Richard D Kolodner, Andrei Kuzminov, Sarah Ae Lambert, Sang Eun Lee, Kyle M Miller, Sergei M
Mirkin, Thomas D Petes, Susan M Rosenberg, Rodney Rothstein, Lorraine S Symington, Pawel
Zawadzki, Nayun Kim, Michael Lisby, Anna Malkova (2019 Jan 7)
Guidelines for DNA recombination and repair studies: Cellular assays of DNA
repair pathways.
Microbial cell (Graz, Austria) : 1-64 : DOI : 10.15698/mic2019.01.664
Résumé
Understanding the plasticity of genomes has been greatly aided by assays for
recombination, repair and mutagenesis. These assays have been developed in microbial
systems that provide the advantages of genetic and molecular reporters that can readily be
manipulated. Cellular assays comprise genetic, molecular, and cytological reporters. The
assays are powerful tools but each comes with its particular advantages and limitations.
Here the most commonly used assays are reviewed, discussed, and presented as the
guidelines for future studies.
G Gentric, Y Kieffer, V Mieulet, O Goundiam, C Bonneau, F Nemati, I Hurbain, G Raposo, T
Popova, MH Stern, V Lallemand-Breitenbach, S Müller, T Cañeque, R Rodriguez, A Vincent-
Salomon, H de Thé, R Rossignol, F Mechta-Grigoriou (2019 Jan 5)
INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 8Publications de l’équipe
UMR3244 – Dynamique de l’information génétique
PML-Regulated Mitochondrial Metabolism Enhances Chemosensitivity in Human
Ovarian Cancers
Cell Metabolism
Résumé
High-grade serous ovarian cancer (HGSOC) remains an unmet medical challenge. Here, we
unravel an unanticipated metabolic heterogeneity in HGSOC. By combining proteomic,
metabolomic, and bioergenetic analyses, we identify two molecular subgroups, low- and
high-OXPHOS. While low-OXPHOS exhibit a glycolytic metabolism, high-OXPHOS HGSOCs rely
on oxidative phosphorylation, supported by glutamine and fatty acid oxidation, and show
chronic oxidative stress. We identify an important role for the PML-PGC-1α axis in the
metabolic features of high-OXPHOS HGSOC. In high-OXPHOS tumors, chronic oxidative stress
promotes aggregation of PML-nuclear bodies, resulting in activation of the transcriptional co-
activator PGC-1α. Active PGC-1α increases synthesis of electron transport chain complexes,
thereby promoting mitochondrial respiration. Importantly, high-OXPHOS HGSOCs exhibit
increased response to conventional chemotherapies, in which increased oxidative stress,
PML, and potentially ferroptosis play key functions. Collectively, our data establish a stress-
mediated PML-PGC-1α-dependent mechanism that promotes OXPHOS metabolism and
chemosensitivity in ovarian cancer.
Mathilde Mathieu, Lorena Martin-Jaular, Grégory Lavieu, Clotilde Théry (2019 Jan 4)
Specificities of secretion and uptake of exosomes and other extracellular
vesicles for cell-to-cell communication.
Nature cell biology : 9-17 : DOI : 10.1038/s41556-018-0250-9
Résumé
The ability of exosomes to transfer cargo from donor to acceptor cells, thereby triggering
phenotypic changes in the latter, has generated substantial interest in the scientific
community. However, the extent to which exosomes differ from other extracellular vesicles
in terms of their biogenesis and functions remains ill-defined. Here, we discuss the current
knowledge on the specificities of exosomes and other types of extracellular vesicles, and
their roles as important agents of cell-to-cell communication.
INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 9You can also read
