Gustave Roussy Comprehensive Cancer Institute

Villejuif, France

Gustave Roussy Comprehensive Cancer Institute

Villejuif, France
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Galluzzi L.,New York Medical College | Galluzzi L.,University of Paris Descartes | Bravo-San Pedro J.M.,University of Paris Descartes | Bravo-San Pedro J.M.,University Pierre and Marie Curie | And 10 more authors.
Nature Reviews Drug Discovery | Year: 2017

Autophagy is central to the maintenance of organismal homeostasis in both physiological and pathological situations. Accordingly, alterations in autophagy have been linked to clinically relevant conditions as diverse as cancer, neurodegeneration and cardiac disorders. Throughout the past decade, autophagy has attracted considerable attention as a target for the development of novel therapeutics. However, such efforts have not yet generated clinically viable interventions. In this Review, we discuss the therapeutic potential of autophagy modulators, analyse the obstacles that have limited their development and propose strategies that may unlock the full therapeutic potential of autophagy modulation in the clinic. © 2017 Macmillan Publishers Limited, part of Springer Nature.


Galluzzi L.,French Institute of Health and Medical Research | Galluzzi L.,University of Paris Descartes | Galluzzi L.,University Pierre and Marie Curie | Galluzzi L.,Gustave Roussy Comprehensive Cancer Institute | And 10 more authors.
Nature Reviews Neuroscience | Year: 2016

Autophagy is an evolutionarily ancient mechanism that ensures the lysosomal degradation of old, supernumerary or ectopic cytoplasmic entities. Most eukaryotic cells, including neurons, rely on proficient autophagic responses for the maintenance of homeostasis in response to stress. Accordingly, autophagy mediates neuroprotective effects following some forms of acute brain damage, including methamphetamine intoxication, spinal cord injury and subarachnoid haemorrhage. In some other circumstances, however, the autophagic machinery precipitates a peculiar form of cell death (known as autosis) that contributes to the aetiology of other types of acute brain damage, such as neonatal asphyxia. Here, we dissect the context-specific impact of autophagy on non-infectious acute brain injury, emphasizing the possible therapeutic application of pharmacological activators and inhibitors of this catabolic process for neuroprotection. © 2016 Macmillan Publishers Limited.


Rodriguez-Arribas M.,University of Extremadura | Yakhine-Diop S.M.S.,University of Extremadura | Pedro J.M.B.-S.,French Institute of Health and Medical Research | Pedro J.M.B.-S.,University of Paris Descartes | And 8 more authors.
Molecular Neurobiology | Year: 2016

Mitochondria-associated membranes (MAMs) are structures that regulate physiological functions between endoplasmic reticulum (ER) and mitochondria in order to maintain calcium signaling and mitochondrial biogenesis. Several proteins located in MAMs, including those encoded by PARK genes and some of neurodegeneration-related proteins (huntingtin, presenilin, etc.), ensure this regulation. In this regard, MAM alteration is associated with neurodegenerative diseases such as Parkinson’s (PD), Alzheimer’s (AD), and Huntington’s diseases (HD) and contributes to the appearance of the pathogenesis features, i.e., autophagy dysregulation, mitochondrial dysfunction, oxidative stress, and lately, neuronal death. Moreover,, ER stress and/or damaged mitochondria can be the cause of these disruptions. Therefore, ER-mitochondria contact structure and function are crucial to multiple cellular processes. This review is focused on the molecular interaction between ER and mitochondria indispensable to MAM formation and on MAM alteration-induced etiology of neurodegenerative diseases. © 2016 Springer Science+Business Media New York


Pietrocola F.,French Institute of Health and Medical Research | Pietrocola F.,University of Paris Descartes | Pietrocola F.,University Pierre and Marie Curie | Pietrocola F.,Gustave Roussy Comprehensive Cancer Institute | And 13 more authors.
Cell Metabolism | Year: 2015

Acetyl-coenzyme A (acetyl-CoA) is a central metabolic intermediate. The abundance of acetyl-CoA in distinct subcellular compartments reflects the general energetic state of the cell. Moreover, acetyl-CoA concentrations influence the activity or specificity of multiple enzymes, either in an allosteric manner or by altering substrate availability. Finally, by influencing the acetylation profile of several proteins, including histones, acetyl-CoA controls key cellular processes, including energy metabolism, mitosis, and autophagy, both directly and via the epigenetic regulation of gene expression. Thus, acetyl-CoA determines the balance between cellular catabolism and anabolism by simultaneously operating as a metabolic intermediate and as a second messenger. Acetyl-coenzyme A (acetyl-CoA) is a key substrate for anabolic reactions and the sole donor of acetyl groups for protein acetylation. In this review, Kroemer and colleagues discuss how acetyl-CoA dictates the balance between cellular catabolism and anabolism by simultaneously operating as a metabolic intermediate and a second messenger. © 2015 Elsevier Inc.


Galluzzi L.,French Institute of Health and Medical Research | Galluzzi L.,University of Paris Descartes | Galluzzi L.,University Pierre and Marie Curie | Galluzzi L.,Gustave Roussy Comprehensive Cancer Institute | And 11 more authors.
Immunity | Year: 2016

Some forms of regulated cell death, such as apoptosis, are precipitated by the activation of cysteine proteases of the caspase family, including caspase 8, 9, and 3. Other caspases, such as caspase 1 and 4, are well known for their pro-inflammatory functions but regulate cell death in a limited number of pathophysiological settings. Accumulating evidence suggests that the most conserved function of mammalian caspases is not to control cell death sensu stricto, but to regulate inflammatory and immune reactions to dying cells and infectious challenges. Here, we review the molecular and cellular mechanisms though which mammalian caspases connect cell-death signaling to the maintenance of organismal homeostasis. © 2016 Elsevier Inc.


Kroemer G.,French Institute of Health and Medical Research | Kroemer G.,University of Paris Descartes | Kroemer G.,University Pierre and Marie Curie | Kroemer G.,Gustave Roussy Comprehensive Cancer Institute | And 4 more authors.
OncoImmunology | Year: 2015

Results from recent clinical trials demonstrate that a combinatorial immunotherapeutic regimen based on 2 distinct checkpoint blockers, namely, the CTLA4-targeting agent ipilimumab and the PD-1-specific molecule nivolumab, causes objective responses in a majority of subjects with advanced melanoma. These findings revolutionize the treatment of a neoplasm that was considered incurable until recently. Nonetheless, announcing the defeat of melanoma appears premature. Indeed, a sizeable fraction of patients does not respond to ipilimumab plus nivolumab, and the long-term efficacy of this immunotherapeutic regimen has not yet been investigated. Moreover, many patients experience severe side effects, calling for the development of strategies that uncouple the efficacy of ipilimumab plus nivolumab from their toxicity. © 2015 Taylor & Francis Group, LLC.


PubMed | New York Medical College and Gustave Roussy Comprehensive Cancer Institute
Type: | Journal: Nature reviews. Immunology | Year: 2016

Immunogenicity depends on two key factors: antigenicity and adjuvanticity. The presence of exogenous or mutated antigens explains why infected cells and malignant cells can initiate an adaptive immune response provided that the cells also emit adjuvant signals as a consequence of cellular stress and death. Several infectious pathogens have devised strategies to control cell death and limit the emission of danger signals from dying cells, thereby avoiding immune recognition. Similarly, cancer cells often escape immunosurveillance owing to defects in the molecular machinery that underlies the release of endogenous adjuvants. Here, we review current knowledge on the mechanisms that underlie the activation of immune responses against dying cells and their pathophysiological relevance.


PubMed | New York Medical College and Gustave Roussy Comprehensive Cancer Institute
Type: Review | Journal: Cancer immunology research | Year: 2016

Accumulating preclinical and clinical evidence indicates that the success of several anticancer agents-including some conventional chemotherapeutics, targeted anticancer agents as well as specific forms of radiotherapy-depends (at least in part) on their ability to stimulate anticancer immune responses. Such immunostimulatory effects can be on-target, i.e., they originate within cancer cells, or off-target, i.e., they develop from a heretofore unsuspected interaction between cancer therapy and the immune system. Here, we briefly discuss the immunologic mechanisms that underlie the efficacy of some forms of cancer therapy, as we highlight the rationale for combining these treatment modalities with immunotherapy to achieve superior therapeutic effects. Cancer Immunol Res; 4(11); 895-902. 2016 AACR.


Gentili M.,French Institute of Health and Medical Research | Kowal J.,French Institute of Health and Medical Research | Tkach M.,French Institute of Health and Medical Research | Satoh T.,French Institute of Health and Medical Research | And 11 more authors.
Science | Year: 2015

Infected cells detect viruses through a variety of receptors that initiate cell-intrinsic innate defense responses. Cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS) is a cytosolic sensor for many DNA viruses and HIV-1. In response to cytosolic viral DNA, cGAS synthesizes the second messenger 2'3'-cyclic GMP-AMP (cGAMP), which activates antiviral signaling pathways. We show that in cells producing virus, cGAS-synthesized cGAMP can be packaged in viral particles and extracellular vesicles. Viral particles efficiently delivered cGAMP to target cells. cGAMP transfer by viral particles to dendritic cells activated innate immunity and antiviral defenses. Finally, we show that cell-free murine cytomegalovirus and Modified Vaccinia Ankara virus contained cGAMP. Thus, transfer of cGAMP by viruses may represent a defense mechanism to propagate immune responses to uninfected target cells.


PubMed | Lytix Biopharma, University of Paris Descartes, Gustave Roussy Comprehensive Cancer Institute and University Pierre and Marie Curie
Type: | Journal: Cell death & disease | Year: 2016

LTX-315 is a cationic amphilytic peptide that preferentially permeabilizes mitochondrial membranes, thereby causing partially BAX/BAK1-regulated, caspase-independent necrosis. Based on the observation that intratumorally injected LTX-315 stimulates a strong T lymphocyte-mediated anticancer immune response, we investigated whether LTX-315 may elicit the hallmarks of immunogenic cell death (ICD), namely (i) exposure of calreticulin on the plasma membrane surface, (ii) release of ATP into the extracellular space, (iii) exodus of HMGB1 from the nucleus, and (iv) induction of a type-1 interferon response. Using a panel of biosensor cell lines and robotized fluorescence microscopy coupled to automatic image analysis, we observed that LTX-315 induces all known ICD characteristics. This conclusion was validated by several independent methods including immunofluorescence stainings (for calreticulin), bioluminescence assays (for ATP), immunoassays (for HMGB1), and RT-PCRs (for type-1 interferon induction). When injected into established cancers, LTX-315 caused a transiently hemorrhagic focal necrosis that was accompanied by massive release of HMGB1 (from close-to-all cancer cells), as well as caspase-3 activation in a fraction of the cells. LTX-315 was at least as efficient as the positive control, the anthracycline mitoxantrone (MTX), in inducing local inflammation with infiltration by myeloid cells and T lymphocytes. Collectively, these results support the idea that LTX-315 can induce ICD, hence explaining its capacity to mediate immune-dependent therapeutic effects.

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