Gabriel Ichim

Gabriel Ichim
Cancer Research Center of Lyon | CRCL · Department of Tumoral Escape

PhD

About

84
Publications
9,255
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2,168
Citations
Citations since 2017
62 Research Items
1774 Citations
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Introduction
Gabriel Ichim currently works at the Department of Tumoral Escape, Cancer Research Center of Lyon (CRCL). Gabriel does research in Cell Death, Molecular and Cell Biology. Their most recent publication is 'Mitochondrial permeabilization engages NF-κB-dependent anti-tumour activity under caspase deficiency.'

Publications

Publications (84)
Article
Full-text available
As a cellular intrinsic mechanism leading to cellular demise, apoptosis was thoroughly characterized from a mechanistic perspective. Nowadays there is an increasing interest in describing the non-cell autonomous or community effects of apoptosis, especially in the context of resistance to cancer treatments. Transitioning from cell-centered to cell...
Article
Full-text available
Metastases are the main cause of death in cancer patients, and platelets are largely known for their contribution in cancer progression. However, targeting platelets is highly challenging given their paramount function in hemostasis. Using a high-throughput screening and platelet-induced breast tumor cell survival (PITCS) assay as endpoint, we iden...
Article
The protease caspase-3 is a key mediator of apoptotic programmed cell death. But weak or transient caspase activity can contribute to neuronal differentiation, axonal pathfinding, and synaptic long-term depression. Despite the importance of sublethal, or nonapoptotic, caspase activity in neurodevelopment and neural plasticity, there has been no sim...
Preprint
As a cellular intrinsic mechanism leading to cellular demise, apoptosis was thoroughly characterized from a mechanistic perspective. Nowadays there is an increasing interest in describing the non-cell autonomous or community effects of apoptosis, especially in the context of resistance to cancer treatments. Transitioning from cell-centered to cell...
Article
Full-text available
Since the Nobel Prize award more than twenty years ago for discovering the core apoptotic pathway in C. elegans, apoptosis and various other forms of regulated cell death have been thoroughly characterized by researchers around the world. Although many aspects of regulated cell death still remain to be elucidated in specific cell subtypes and disea...
Article
Full-text available
Micronuclei are DNA-containing structures separate from the nucleus found in cancer cells. Micronuclei are recognized by the immune sensor axis cGAS/STING, driving cancer metastasis. The mitochondrial apoptosis apparatus can be experimentally triggered to a non-apoptotic level, and this can drive the appearance of micronuclei through the Caspase-ac...
Article
Mitochondrial dysfunction is interconnected with cancer. Nevertheless, how defective mitochondria promote cancer is poorly understood. We find that mitochondrial dysfunction promotes DNA damage under conditions of increased apoptotic priming. Underlying this process, we reveal a key role for mitochondrial dynamics in the regulation of DNA damage an...
Article
Full-text available
Glioblastoma (GBM) is the most prevalent malignant primary brain tumour in adults. GBM typically has a poor prognosis, mainly due to a lack of effective treatment options leading to tumour persistence or recurrence. We investigated the therapeutic potential of targeting anti-apoptotic BCL-2 proteins in GBM. Levels of anti-apoptotic BCL-xL and MCL-1...
Article
Full-text available
Mechanical stress is known to fuel several hallmarks of cancer, ranging from genome instability to uncontrolled proliferation or invasion. Cancer cells are constantly challenged by mechanical stresses not only in the primary tumour but also during metastasis. However, this latter has seldom been studied with regards to mechanobiology, in particular...
Preprint
Mitochondrial dysfunction is interconnected with cancer. Nevertheless, how defective mitochondria promote cancer is poorly understood. We find that mitochondrial dysfunction promotes DNA damage under conditions of increased apoptotic priming. Underlying this process, we reveal a key role for mitochondrial dynamics in the regulation of DNA damage an...
Preprint
Full-text available
Mechanical stress is known to fuel several hallmarks of cancer, ranging from genome instability to uncontrolled proliferation or invasion. Cancer cells are constantly challenged by mechanical stresses not only in the primary tumour but also during metastasis. However, this latter has seldom been studied with regards to mechanobiology, in particular...
Preprint
Full-text available
IDH wild-type glioblastoma (GBM) is the most prevalent malignant primary brain tumour in adults. GBM typically has a poor prognosis, mainly due to a lack of effective treatment options leading to tumour persistence or recurrence. Tackling this, we investigated the therapeutic potential of targeting anti-apoptotic BCL-2 proteins in GBM. Levels of an...
Article
Full-text available
In cancer cells only, TLR3 acquires death receptor properties by efficiently triggering the extrinsic pathway of apoptosis with Caspase-8 as apical protease. Here, we demonstrate that in the absence of Caspase-8, activation of TLR3 can trigger a form of programmed cell death, which is distinct from classical apoptosis. When TLR3 was activated in th...
Article
Full-text available
Mammalian cytosine DNA methylation (5mC) is associated with the integrity of the genome and the transcriptional status of nuclear DNA. Due to technical limitations, it has been less clear if mitochondrial DNA (mtDNA) is methylated and whether 5mC has a regulatory role in this context. Here, we used bisulfite-independent single-molecule sequencing o...
Article
Significance TAT-RasGAP 317–326 can lyse cancer cells in a manner distinct from known programmed cell death pathways through its ability to target specific plasma membrane lipids. The killing properties of this peptide may therefore be difficult for cancer cells to alleviate through resistance-building alterations within known regulated cell death...
Article
Full-text available
Apoptosis exerts noncanonical pro‐oncogenic effects. Firstly, apoptotic cells release various paracrine factors that instruct cancer cells to proliferate, develop drug resistance, or avoid immune surveillance. Secondly, minority MOMP, which is characterized by permeabilization of few mitochondria and nonlethal caspase activation, triggers DNA damag...
Article
Full-text available
Glioblastoma (GBM) is one of the cancers with the worst prognosis, despite huge efforts to understand its unusual heterogeneity and aggressiveness. This is mainly due to glioblastoma stem cells (GSCs), which are also responsible for the frequent tumor recurrence following surgery, chemotherapy or radiotherapy. In this study, we investigate the expr...
Preprint
Full-text available
Cytosine DNA methylation in the CpG context (5mCpG) is associated with the transcriptional status of nuclear DNA. Due to technical limitations, it has been less clear if mitochondrial DNA (mtDNA) is methylated and whether 5mCpG has a regulatory role in this context. The main aim of this work was to develop and validate a novel tool for determining...
Article
Full-text available
Apoptosis is vital for the correct morphogenesis of multi-cellular organisms. However, like most physiological programs, the cell’s ability to commit suicide is hijacked by cancer in its own proliferative and invasive interest. We recently showed that inefficient execution of apoptosis (or failed apoptosis) is used by cancer to boost invasiveness.
Article
Full-text available
Triggering apoptosis remains an efficient strategy to treat cancer. However, apoptosis is no longer a final destination since cancer cells can undergo partial apoptosis without dying. Recent evidence shows that partial mitochondrial permeabilization and non-lethal caspase activation occur under certain circumstances, although it remains unclear how...
Article
Full-text available
Epigenetic deregulation of gene transcription is central to cancer cell plasticity and malignant progression, but remains poorly understood. We found that the uncharacterized epigenetic factor Chromodomain on Y-like 2 (CDYL2) is commonly over-expressed in breast cancer, and that high CDYL2 levels correlate with poor prognosis. Supporting a function...
Preprint
Full-text available
Glioblastoma is one of the cancers with the worst prognosis, despite huge efforts to understand its unusual heterogeneity and aggressiveness. These are mainly attributable to glioblastoma stem cells, which are also responsible for the frequent tumour recurrence following surgery or chemo/radiotherapy. We report here that tumorspheres derived from t...
Article
The Sonic Hedgehog (SHH) pathway plays a key role in cancer. Alterations of SHH canonical signaling, causally linked to tumor progression, have become rational targets for cancer therapy. However, Smoothened (SMO) inhibitors have failed to show clinical benefit in patients with cancers displaying SHH autocrine/paracrine expression. We reported earl...
Preprint
Full-text available
TLR3 converts in cancer cells from an inflammatory to a death receptor and TLR3-induced cell death activates the extrinsic apoptosis pathway. Here, we demonstrate that activation of TLR3 triggers a form lysosomal cell death. Following the combinational treatment of IFN-1/poly(I:C) of the caspase-8 deficient neuroblastoma cell line SH-SY5Y, lysosome...
Preprint
Full-text available
Triggering apoptosis remains an efficient strategy to treat cancer. However, apoptosis is no longer a final destination, since cells can undergo partial apoptosis without dying. Recent evidence shows that partial mitochondrial permeabilization and non-lethal caspase activation occur under certain circumstances, though it remains unclear how failed...
Article
Full-text available
Background Apoptosis, the most well-known type of programmed cell death, can induce in a paracrine manner a proliferative response in neighboring surviving cells called apoptosis-induced proliferation (AiP). While having obvious benefits when triggered in developmental processes, AiP is a serious obstacle in cancer therapy, where apoptosis is frequ...
Article
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The neurotrophin-3 (NT-3) receptor tropomyosin receptor kinase C (TrkC/NTRK3) has been described as a dependence receptor and, as such, triggers apoptosis in the absence of its ligand NT-3. This proapoptotic activity has been proposed to confer a tumor suppressor activity to this classic tyrosine kinase receptor (RTK). By investigating interacting...
Data
TrkC-KF is translocated to the nucleus by importins and has no intrinsic transcriptional activity per se. (A) SHEP cells transfected with either control plasmid, TrkC-KF-Flag, TrkC-FL, or Neo-IC were fractionated into cytoplasmic (Cytoplasm, marker: GAPDH) and nuclear (Nucleus, marker: histone) fractions. Input corresponds to the construct expressi...
Data
TrkC-KF and Hey1 cooperate to inhibit MDM2 transcription by direct binding on its promoter. (A) Proximity ligation assay (DuoLink) using an anti-MDM2 antibody (recognizing endogenous MDM2) on SHEP cells transfected with TrkC-KF-Flag (anti-Flag antibody) or not transfected (anti-Hey1 antibody targeting endogenous Hey1 and anti-p53 antibody targeting...
Data
Primers and probes used for ChIP. RT-QPCR was performed using the TaqMan technique, requiring the indicated probes (Universal Probe Library, Roche Applied Science). ChIP, chromatin immunoprecipitation; RT-QPCR, quantitative real-time PCR. (XLS)
Data
Hey1 is necessary for TrkC-KF-induced p53 stabilization. (A) Quantification of the western blot presented in (Fig 4A), which has been reproduced and quantified 3 times: Signal of the anti-p53 western blot is compared to anti-Actin signal. Data represent values indexed to control, mean ± SEM (n = 3). *p < 0.05, **p < 0.01. t test. (B) p53 expression...
Data
TrkC-KF associates specifically to the transcription factor Hey1 in the nucleus. (A) Mouse Hey1, Hey2, and HeyL mRNA expression were assessed in N2A cells transfected with an siRNA control or an siRNA targeting Hey1. Data represent values (arbitrary units) relative to HPRT mRNA expression (housekeeping gene). (B) Hey1 expression was assessed by wes...
Data
Hey1 is essential for the cell death mediated by TrkC. (A) TrkA, TrkB, TrkC, NGF, BDNF, and NT-3 mRNA expression was assessed by RT-QPCR on CLB-Ga, LAN6, and SHEP cells relative to HPRT mRNA expression (housekeeping gene). A representative experiment is shown. (B) Immunofluorescence staining using Cy3 performed on LAN6 cells transfected or with the...
Data
Primers and probes used for RT-QPCR. RT-QPCR was performed using the TaqMan technique, requiring the indicated probes (Universal Probe Library, Roche Applied Science). RT-QPCR, quantitative real-time PCR. (XLS)
Data
NB tumors gain a selective advantage when the TrkC apoptotic pathway is silenced. (A, B) TrkC and Hey1 expression in neuroblastic tumors. Dot plots of TrkC (A) and Hey1 (B) mRNA expression values in neuroblastic tumor samples stages 1 to 3 versus stage 4 analyzed using the Agilent microarray 44K (T. Wolf cohort [54], 649 samples, NB1–3 [n = 357], a...
Data
Schematic representation of TrkC proapoptotic pathway. When TrkC is deprived of its ligand, its intracellular domain is double cleaved by caspase, and the released fragment is called TrkC-KF. TrkC-KF is shuttled into the nucleus by importins and interacts there with Hey1 bHLH transcription factor. Hey1 and TrkC-KF bind jointly on MDM2 promoter and...
Article
Caspase-8 is involved in a number of cellular functions, with the most well established being the control of cell death. Yet caspase-8 is unique among the caspases in that it acts as an environmental sensor, transducing a range of signals to cells, modulating responses that extend far beyond simple survival. Ranging from the control of apoptosis an...
Article
Apoptosis represents a key anti-cancer therapeutic effector mechanism. During apoptosis, mitochondrial outer membrane permeabilization (MOMP) typically kills cells even in the absence of caspase activity. Caspase activity can also have a variety of unwanted consequences that include DNA damage. We therefore investigated whether MOMP-induced caspase...
Article
Full-text available
Apoptosis represents a key anti-cancer therapeutic effector mechanism. During apoptosis, mitochondrial outer membrane permeabilization (MOMP) typically kills cells even in the absence of caspase activity. Caspase activity can also have a variety of unwanted consequences that include DNA damage. We therefore investigated whether MOMP-induced caspase...
Article
Full-text available
Mitochondria are not only the 'powerhouse' of the cell; they are also involved in a multitude of processes that include calcium storage, the cell cycle and cell death. Traditional means of investigating mitochondrial importance in a given cellular process have centered upon depletion of mtDNA through chemical or genetic means. Although these method...
Article
Full-text available
Apoptotic cell death is widely considered a positive process that both prevents and treats cancer. Although undoubtedly having a beneficial role, paradoxically, apoptosis can also cause unwanted effects that may even promote cancer. In this Opinion article we highlight some of the ways by which apoptosis can exert oncogenic functions. We argue that...
Chapter
Full-text available
Most apoptotic cell death events in the body occur via engagement of the mitochondrial pathway of apoptosis. This signaling pathway involves the regulated release, by members of the BCL2 protein family, of mitochondrial proteins following mitochondrial outer membrane permeabilization (MOMP). This in turn activates caspase proteases, generally leadi...
Article
Full-text available
Most apoptotic stimuli require mitochondrial outer membrane permeabilization (MOMP) in order to execute cell death. As such, MOMP is subject to tight control by Bcl-2 family proteins. We have developed a powerful new technique to investigate Bcl-2-mediated regulation of MOMP. This method, called mito-priming, uses co-expression of pro- and anti-apo...
Data
SVEC cells stably expressing eGFP-tBID 2A BCL-xL were treated with 10μM ABT-737 and analysed for cell viability by SYTOX Green exclusion and IncuCyte cell imaging every 5 minutes for 21 hours.
Data
SVEC cells stably expressing eGFP-tBID 2A BCL-xL were transfected with SMAC-mCherry. Following treatment with 10μM ABT-737, images were acquired on a Nikon A1R confocal instrument every 5 minutes for 1 hour.
Data
SVEC cells stably expressing eGFP-tBID 2A BCL-xL were treated with 10μM ABT-737 and analysed for cell viability by Annexin V staining (purple). Images were acquired on a Nikon A1R confocal instrument every 5 minutes for 1.5 hour.
Article
Full-text available
During apoptosis, the mitochondrial outer membrane is permeabilized, leading to the release of cytochrome c that activates downstream caspases. Mitochondrial outer membrane permeabilization (MOMP) has historically been thought to occur synchronously and completely throughout a cell, leading to rapid caspase activation and apoptosis. Using a new ima...
Article
Full-text available
Apoptosis and necroptosis are 2 major, yet distinct, forms of regulated cell death. Whereas apoptosis requires caspase protease function, necroptosis requires activation of the receptor interacting protein kinases 1 (RIPK1) and RIPK3. Following activation, RIPK3 phosphorylates mixed-lineage kinase domain-like (MLKL), leading to cell death. Apoptosi...
Article
Full-text available
The Bcl-2 proteins Bax and Bak can permeabilize the outer mitochondrial membrane and commit cells to apoptosis. Pro-survival Bcl-2 proteins control Bax by constant retrotranslocation into the cytosol of healthy cells. The stabilization of cytosolic Bax raises the question whether the functionally redundant but largely mitochondrial Bak shares this...
Article
Full-text available
Regulated, programmed cell death is crucial for all multicellular organisms. Cell death is essential in many processes, including tissue sculpting during embryogenesis, development of the immune system and destruction of damaged cells. The best-studied form of programmed cell death is apoptosis, a process that requires activation of caspase proteas...
Article
Full-text available
Programmed necrosis (or necroptosis) is a form of cell death triggered by the activation of receptor interacting protein kinase-3 (RIPK3). Several reports have implicated mitochondria and mitochondrial reactive oxygen species (ROS) generation as effectors of RIPK3-dependent cell death. Here, we directly test this idea by employing a method for the...
Article
Full-text available
The receptor tyrosine kinase Met and its ligand, the hepatocyte growth factor, are essential to embryonic development, whereas the deregulation of Met signaling is associated with tumorigenesis. While ligand-activated Met promotes survival, caspase-dependent generation of the p40 Met fragment leads to apoptosis induction - hallmark of the dependenc...
Article
Full-text available
The neurotrophin receptor TrkC was recently identified as a dependence receptor, and, as such, it triggers apoptosis in the absence of its ligand, NT-3. The molecular mechanism for apoptotic engagement involves the double cleavage of the receptor's intracellular domain, leading to the formation of a proapoptotic "killer" fragment (TrkC KF). Here, w...