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See detailCrosstalk between different family members: IL27 recapitulates IFNγ responses in HCC cells, but is inhibited by IL6-type cytokines
Rolvering, Catherine UL; Zimmer, Andreas; Kozar, Ines UL et al

in BBA Molecular Cell Research (2017)

Interleukin-27 (IL27) is a type-I-cytokine of the IL6/IL12 family predominantly secreted by activated macrophages and dendritic cells. In the liver, IL27 expression was observed to be upregulated in ... [more ▼]

Interleukin-27 (IL27) is a type-I-cytokine of the IL6/IL12 family predominantly secreted by activated macrophages and dendritic cells. In the liver, IL27 expression was observed to be upregulated in patients with hepatitis B, and sera of hepatocellular carcinoma (HCC) patients contain significantly elevated levels of IL27 compared to healthy controls or patients with hepatitis and/or liver cirrhosis. In this study, we show that IL27 induces STAT1 and STAT3 phosphorylation in 5 HCC lines and 3 different types of non-transformed liver cells. We were especially interested in the relevance of the IL27-induced STAT3 activation in liver cells. Thus, we compared the IL27 responses with those induced by IFNγ (STAT1-dominated response) or IL6-type cytokines (IL6, hyper-IL6 (hy-IL6) or OSM) (STAT3-dominated response) by microarray analysis and find that in HCC cells, IL27 induces an IFNγ-like, STAT1-dependent transcriptional response, but we do not find an effective STAT3-dependent response. Validation experiments corroborate the finding from the microarray evaluation. Interestingly, the availability of STAT1 seems critical in the shaping of the IL27 response, as the siRNA knock-down of STAT1 revealed the ability of IL27 to induce the acute-phase protein γ-fibrinogen, a typical IL6 family characteristic. Moreover, we describe a crosstalk between the signaling of IL6-type cytokines and IL27: responses to the gp130-engaging cytokine IL27 (but not those to IFNs) can be inhibited by IL6-type cytokine pre-stimulation, likely by a SOCS3-mediated mechanism. Thus, IL27 recapitulates IFNγ responses in liver cells, but differs from IFNγ by its sensitivity to SOCS3 inhibition. [less ▲]

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See detailTumor-Initiating Cells: a criTICal review of isolation approaches and new challenges in targeting strategies
Baig, Komal UL; Ullmann, Pit UL; Haan, Serge UL et al

in Molecular Cancer (2017)

Most cancers contain a subpopulation of highly tumorigenic cells, known as cancer stem cells (CSCs) or tumor-initiating cells (TICs). Targeting TICs may be essential to achieve cure, because of their self ... [more ▼]

Most cancers contain a subpopulation of highly tumorigenic cells, known as cancer stem cells (CSCs) or tumor-initiating cells (TICs). Targeting TICs may be essential to achieve cure, because of their self-renewal and tumorigenic properties as well as their resistance to conventional therapies. Despite significant advances in TIC biology, their isolation and identification remain largely disputed and incompletely established. In this review, we discuss the latest developments in isolation and culturing approaches of TICs, with focus on colorectal cancer (CRC). We feature recent findings on TIC-relevant signaling pathways and the metabolic identity of TICs, as well as their current clinical implications. Lastly, we highlight the influence of inter- and intra-tumoral heterogeneity on TIC function and targeting approaches. [less ▲]

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See detailFrom meta-genomics to causality: Understanding the role of colon cancer-associated bacteria in colorectal cancer
Ternes, Dominik UL; Wilmes, Paul UL; Letellier, Elisabeth UL et al

Poster (2017, February 05)

The human gastrointestinal tract is home for trillions of bacteria that influence homeostasis and health in a complex biological system: the gut microbiome. Accumulating evidence suggests that a state of ... [more ▼]

The human gastrointestinal tract is home for trillions of bacteria that influence homeostasis and health in a complex biological system: the gut microbiome. Accumulating evidence suggests that a state of pathological imbalance in the microbiome (dysbiosis) is present in patients suffering from colorectal cancer (CRC). To date, microbiome studies identified specific bacteria being associated with dysbiosis in CRC. Some of these bacteria (e.g. Fusobacteria) directly or indirectly interact with cancer and immune cells of their host. However, current studies only focused on certain microbes in detail, hence, their role in the etiology of the disease remains elusive. Accordingly, my project investigates the role of CRC-associated bacteria in tumor initiation and progression while addressing the question: which and what kind of microbes interact with, favor, or can cause CRC? In a first step, we identified CRC-associated bacteria, enriched at the tumor site of Luxembourgish CRC patients. By using Fusobacterium nucleatum as our study model, we predicted and optimized bacterial growth (media) in silico by using a genome-scale metabolic reconstruction model for a constraint-based modelling approach. Next, we assessed bacterial growth and metabolism in the optimized growth medium by using flow cytometry and mass spectrometry. Finally, we co-cultured the bacteria together with primary patient-derived cultures in the recently developed, microfluidics-based, human-microbial cross-talk model (HuMiX) [1]. As part of our ongoing validations, we infected patient-derived, healthy and cancerous 3D colonic organoids with our bacterial candidate. This workflow enables us to analyze pro-tumorigenic capacities of CRC-associated bacteria on healthy and cancerous colonocytes. It will serve as a promising tool for future analysis of host-microbial interaction mechanisms of various CRC-associated bacteria on a transcriptomic, proteomic, and metabolomic level. [1] Shah P, Fritz JV, Glaab E, Desai MS, Greenhalgh K et al. (2016) A microfluidics-based in vitro model of the gastrointestinal human-microbe interface. Nature communications 7: 11535. [less ▲]

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See detailInsights into ligand stimulation effects on gastro-intestinal stromal tumors signalling.
Bahlawane, Christelle; Schmitz, Martine UL; Letellier, Elisabeth UL et al

in Cell Signal (2017)

Mutations in KIT or PDGFRA are responsible for >85% of gastrointestinal stromal tumors. The introduction of imatinib in the GIST therapy scheme revolutionized the patient outcome. Unfortunately, the ... [more ▼]

Mutations in KIT or PDGFRA are responsible for >85% of gastrointestinal stromal tumors. The introduction of imatinib in the GIST therapy scheme revolutionized the patient outcome. Unfortunately, the therapy allows the disease stabilization instead of curation. Furthermore the resistance to the inhibitor arises in most cases within two first years of therapy. A thorough investigation of the signalling pathways activated by the major PDGFRA and KIT mutants encountered in the GIST landscape allowed to identify striking differences between the two receptor tyrosine kinases. PDGFRA mutants were not responsive to their ligand, PDGFAA, and displayed a high constitutive kinase activity. In contrast, all KIT mutants retained, in addition to their constitutive activation, the ability to be stimulated by their ligand. Kit mutants displayed a lower intrinsic kinase activity relative to PDGFRA mutants, while the KIT Exon 11 deletion mutant exhibited the highest intrinsic kinase activity among KIT mutants. At the transcriptomic level, the MAPK pathway was established as the most prominent activated pathway, which is commonly up-regulated by all PDGFRA and KIT mutants. Inhibition of this pathway, using the MEK inhibitor PD0325901, reduced the proliferation of GIST primary cells at nanomolar concentrations. Altogether, our data demonstrate the high value of MEK inhibitors for combination therapy in GIST treatment and more importantly the interest of evaluating the SCF expression profile in GIST patients presenting KIT mutations. [less ▲]

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See detailData on quantification of signaling pathways activated by KIT and PDGFRA mutants.
Bahlawane, Christelle; Schmitz, Martine UL; Letellier, Elisabeth UL et al

in Data in Brief (2016), (9), 828-838

The present data are related to the article entitled "Insights into ligand stimulation effects on gastro-intestinal stromal tumors signaling" (C. Bahlawane, M. Schmitz, E. Letellier, K. Arumugam, N. Nicot ... [more ▼]

The present data are related to the article entitled "Insights into ligand stimulation effects on gastro-intestinal stromal tumors signaling" (C. Bahlawane, M. Schmitz, E. Letellier, K. Arumugam, N. Nicot, P.V. Nazarov, S. Haan, 2016) [1]. Constitutive and ligand-derived signaling pathways mediated by KIT and PDGFRA mutated proteins found in gastrointestinal stromal tumors (GIST) were compared. Expression of mutant proteins was induced by doxycycline in an isogenic background (Hek293 cells). Kit was identified by FACS at the cell surface and found to be quickly degraded or internalized upon SCF stimulation for both Kit Wild type and Kit mutant counterparts. Investigation of the main activated pathways in GIST unraveled a new feature specific for oncogenic KIT mutants, namely their ability to be further activated by Kit ligand, the stem cell factor (scf). We were also able to identify the MAPK pathway as the most prominent target for a common inhibition of PDGFRA and KIT oncogenic signaling. Western blotting and micro-array analysis were applied to analyze the capacities of the mutant to induce an effective STATs response. Among all Kit mutants, only Kit Ex11 deletion mutant was able to elicit an effective STATs response whereas all PDGFRA were able to do so. [less ▲]

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See detailHypoxia-responsive miR-210 promotes self-renewal capacity of colon tumor-initiating cells by repressing ISCU and by inducing lactate production
Ullmann, Pit UL; qureshi-baig, komal; Rodriguez, Fabien UL et al

in Oncotarget (2016), 7(40), 97-114

Low oxygen concentrations (hypoxia) are known to affect the cellular metabolism and have been suggested to regulate a subpopulation of cancer cells with tumorigenic properties, the so-called tumor ... [more ▼]

Low oxygen concentrations (hypoxia) are known to affect the cellular metabolism and have been suggested to regulate a subpopulation of cancer cells with tumorigenic properties, the so-called tumor-initiating cells (TICs). To better understand the mechanism of hypoxia-induced TIC activation, we set out to study the role of hypoxia-responsive miRNAs in recently established colon cancer patientderived TICs. We were able to show that low oxygen concentrations consistently lead to the upregulation of miR-210 in different primary TIC-enriched cultures. Both stable overexpression of miR-210 and knockdown of its target gene ISCU resulted in enhanced TIC self-renewal. We could validate the tumorigenic properties of miR- 210 in in vivo experiments by showing that ectopic expression of miR-210 results in increased tumor incidence. Furthermore, enhanced miR-210 expression correlated with reduced TCA cycle activity and increased lactate levels. Importantly, by blocking lactate production via inhibition of LDHA, we could reverse the promoting effect of miR-210 on self-renewal capacity, thereby emphasizing the regulatory impact of the glycolytic phenotype on colon TIC properties. Finally, by assessing expression levels in patient tissue, we could demonstrate the clinical relevance of the miR-210/ISCU signaling axis for colorectal carcinoma. Taken together, our study highlights the importance of hypoxia-induced miR-210 in the regulation of colon cancer initiation. [less ▲]

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See detailWhat Do We Learn from Spheroid Culture Systems? Insights from Tumorspheres Derived from Primary Colon Cancer Tissue.
Baig, Komal UL; Ullmann, Pit UL; Rodriguez, Fabien UL et al

in PLoS ONE (2016), 11

Due to their self-renewal and tumorigenic properties, tumor-initiating cells (TICs) have been hypothesized to be important targets for colorectal cancer (CRC). However the study of TICs is hampered by the ... [more ▼]

Due to their self-renewal and tumorigenic properties, tumor-initiating cells (TICs) have been hypothesized to be important targets for colorectal cancer (CRC). However the study of TICs is hampered by the fact that the identification and culturing of TICs is still a subject of extensive debate. Floating three-dimensional spheroid cultures (SC) that grow in serum-free medium supplemented with growth factors are supposed to be enriched in TICs. We generated SC from fresh clinical tumor specimens and compared them to SC isolated from CRC cell-lines as well as to adherent differentiated counterparts. Patient-derived SC display self-renewal capacity and can induce serial transplantable tumors in immuno-deficient mice, which phenotypically resemble the tumor of origin. In addition, the original tumor tissue and established SC retain several similar CRC-relevant mutations. Primary SC express key stemness proteins such as SOX2, OCT4, NANOG and LGR5 and importantly show increased chemoresistance ability compared to their adherent differentiated counterparts and to cell line-derived SC. Strikingly, cells derived from spheroid or adherent differentiating culture conditions displayed similar self-renewal capacity and equally formed tumors in immune-deficient mice, suggesting that self-renewal and tumor-initiation capacity of TICs is not restricted to phenotypically immature spheroid cells, which we describe to be highly plastic and able to reacquire stem-cell traits even after long differentiation processes. Finally, we identified two genes among a sphere gene expression signature that predict disease relapse in CRC patients. Here we propose that SC derived from fresh patient tumor tissue present interesting phenotypic features that may have clinical relevance for chemoresistance and disease relapse and therefore represent a valuable tool to test for new CRC-therapies that overcome drug resistance. [less ▲]

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See detailSOCS2: physiological and pathological functions.
Letellier, Elisabeth UL; Haan, Serge UL

in Frontiers in Bioscience (Elite Edition) (2016), 8

Suppressors of cytokine signalling (SOCS) proteins are modulators of cytokine and growth factor signalling whose aberrant regulation has been linked to a variety of inflammatory and neoplastic diseases ... [more ▼]

Suppressors of cytokine signalling (SOCS) proteins are modulators of cytokine and growth factor signalling whose aberrant regulation has been linked to a variety of inflammatory and neoplastic diseases. SOCS proteins are able to act as substrate-recruiting component of E3-ubiquitin ligase complexes and target interacting proteins for degradation. At least some of the family members can also directly inhibit tyrosine kinases such as Janus Kinases (JAK). The most studied family members, CIS, SOCS1, SOCS2 and SOCS3 are important regulators of the JAK-STAT pathway. Here, we focus on SOCS2 and review its biological function as well as its implication in pathological processes. Furthermore, we take advantage of the known crystal structures of SOCS2 to discuss the potential effects of a selection of SOCS2 mutations that were identified in tumour tissues. [less ▲]

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See detailIdentification of SOCS2 and SOCS6 as biomarkers in human colorectal cancer.
Letellier, Elisabeth UL; Schmitz, Martine UL; Baig, Komal UL et al

in British journal of cancer (2014), 111(4), 726-35

BACKGROUND: Over the past years, some members of the family of suppressor of cytokine signalling (SOCS) proteins have emerged as potential tumour suppressors. This study aimed at investigating the ... [more ▼]

BACKGROUND: Over the past years, some members of the family of suppressor of cytokine signalling (SOCS) proteins have emerged as potential tumour suppressors. This study aimed at investigating the clinical significance of SOCS proteins in colorectal carcinoma (CRC). METHODS: We integrated publicly available microarray expression data on CRC in humans, analysed the expression pattern of SOCSs and assessed the predictive power of SOCS2 and SOCS6 for diagnostic purposes by generating receiver operating characteristic curves. Using laser microdissected patient material we assessed SOCS expression on RNA and protein levels as well as their methylation status in an independent CRC patient cohort. Finally, we investigated the prognostic value of SOCS2 and SOCS6. RESULTS: The meta-analysis as well as the independent patient cohort analysis reveal a stage-independent downregulation of SOCS2 and SOCS6 and identify both molecules as diagnostic biomarkers for CRC. We demonstrate a different methylation pattern within the SOCS2 promoter between tumour tissue and normal control tissue in 25% of CRC patients. Furthermore, early CRC stage patients with low expression of SOCS2 display significantly shorter disease-free survival. CONCLUSIONS: Our data offers evidence that SOCS2 and SOCS6 levels are reduced in CRC and may serve as diagnostic biomarkers for CRC patients. [less ▲]

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See detailThe hematopoietic factor granulocyte-colony stimulating factor improves outcome in experimental spinal cord injury.
Pitzer, Claudia; Klussmann, Stefan; Krüger, Carola et al

in Journal of Neurochemistry (2010), 113

Granulocyte-colony stimulating factor (G-CSF) is a potent hematopoietic factor that drives differentiation of neutrophilic granulocytes. We have recently shown that G-CSF also acts as a neuronal growth ... [more ▼]

Granulocyte-colony stimulating factor (G-CSF) is a potent hematopoietic factor that drives differentiation of neutrophilic granulocytes. We have recently shown that G-CSF also acts as a neuronal growth factor, protects neurons in vitro and in vivo, and has regenerative potential in various neurological disease models. Spinal cord injury (SCI) following trauma or secondary to skeletal instability is a terrible condition with no effective therapies available at present. In this study, we show that the G-CSF receptor is up-regulated upon experimental SCI and that G-CSF improves functional outcome in a partial dissection model of SCI. G-CSF significantly decreases apoptosis in an experimental partial spinal transsection model in the mouse and increases expression of the anti-apoptotic G-CSF target gene Bcl-X(L). In vitro, G-CSF enhances neurite outgrowth and branching capacity of hippocampal neurons. In vivo, G-CSF treatment results in improved functional connectivity of the injured spinal cord as measured by Mn(2+)-enhanced MRI. G-CSF also increased length of the dorsal corticospinal tract and density of serotonergic fibers cranial to the lesion center. Mice treated systemically with G-CSF as well as transgenic mice over-expressing G-CSF in the CNS exhibit a strong improvement in functional outcome as measured by the BBB score and gridwalk analysis. We show that G-CSF improves outcome after experimental SCI by counteracting apoptosis, and enhancing connectivity in the injured spinal cord. We conclude that G-CSF constitutes a promising and feasible new therapy option for SCI. [less ▲]

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See detailCD95-ligand on peripheral myeloid cells activates Syk kinase to trigger their recruitment to the inflammatory site.
Letellier, Elisabeth UL; Kumar S; Sancho-Martinez I et al

in Immunity (2010), 32

Injury to the central nervous system initiates an uncontrolled inflammatory response that results in both tissue repair and destruction. Here, we showed that, in rodents and humans, injury to the spinal ... [more ▼]

Injury to the central nervous system initiates an uncontrolled inflammatory response that results in both tissue repair and destruction. Here, we showed that, in rodents and humans, injury to the spinal cord triggered surface expression of CD95 ligand (CD95L, FasL) on peripheral blood myeloid cells. CD95L stimulation of CD95 on these cells activated phosphoinositide 3-kinase (PI3K) and metalloproteinase-9 (MMP-9) via recruitment and activation of Syk kinase, ultimately leading to increased migration. Exclusive CD95L deletion in myeloid cells greatly decreased the number of neutrophils and macrophages infiltrating the injured spinal cord or the inflamed peritoneum after thioglycollate injection. Importantly, deletion of myeloid CD95L, but not of CD95 on neural cells, led to functional recovery of spinal injured animals. Our results indicate that CD95L acts on peripheral myeloid cells to induce tissue damage. Thus, neutralization of CD95L should be considered as a means to create a controlled beneficial inflammatory response. [less ▲]

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See detailThe death receptor CD95 activates adult neural stem cells for working memory formation and brain repair.
Corsini NS; Sancho-Martinez I; Laudenklos S et al

in Cell Stem Cell (2009), 5

Adult neurogenesis persists in the subventricular zone and the dentate gyrus and can be induced upon central nervous system injury. However, the final contribution of newborn neurons to neuronal networks ... [more ▼]

Adult neurogenesis persists in the subventricular zone and the dentate gyrus and can be induced upon central nervous system injury. However, the final contribution of newborn neurons to neuronal networks is limited. Here we show that in neural stem cells, stimulation of the "death receptor" CD95 does not trigger apoptosis but unexpectedly leads to increased stem cell survival and neuronal specification. These effects are mediated via activation of the Src/PI3K/AKT/mTOR signaling pathway, ultimately leading to a global increase in protein translation. Induction of neurogenesis by CD95 was further confirmed in the ischemic CA1 region, in the naive dentate gyrus, and after forced expression of CD95L in the adult subventricular zone. Lack of hippocampal CD95 resulted in a reduction in neurogenesis and working memory deficits. Following global ischemia, CD95-mediated brain repair rescued behavioral impairment. Thus, we identify the CD95/CD95L system as an instructive signal for ongoing and injury-induced neurogenesis. [less ▲]

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See detailYes and PI3K bind CD95 to signal invasion of glioblastoma.
Kleber, Susanne; Sancho-Martinez I; Wiestler B et al

in Cancer Cell (2008), 13

Invasion of surrounding brain tissue by isolated tumor cells represents one of the main obstacles to a curative therapy of glioblastoma multiforme. Here we unravel a mechanism regulating glioma ... [more ▼]

Invasion of surrounding brain tissue by isolated tumor cells represents one of the main obstacles to a curative therapy of glioblastoma multiforme. Here we unravel a mechanism regulating glioma infiltration. Tumor interaction with the surrounding brain tissue induces CD95 Ligand expression. Binding of CD95 Ligand to CD95 on glioblastoma cells recruits the Src family member Yes and the p85 subunit of phosphatidylinositol 3-kinase to CD95, which signal invasion via the glycogen synthase kinase 3-beta pathway and subsequent expression of matrix metalloproteinases. In a murine syngeneic model of intracranial GBM, neutralization of CD95 activity dramatically reduced the number of invading cells. Our results uncover CD95 as an activator of PI3K and, most importantly, as a crucial trigger of basal invasion of glioblastoma in vivo. [less ▲]

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See detailSpinal cord injuries entering the Fas(t) lane.
Letellier, Elisabeth UL; Martin-Villalba, Ana

in Neurosurgery (2007), 6

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See detailManganese-enhanced magnetic resonance imaging for in vivo assessment of damage and functional improvement following spinal cord injury in mice.
Stieltjes B,; Klussmann S; Bock M et al

in Magn Reson Med (2006), 5

In past decades, much effort has been invested in developing therapies for spinal injuries. Lack of standardization of clinical read-out measures, however, makes direct comparison of experimental ... [more ▼]

In past decades, much effort has been invested in developing therapies for spinal injuries. Lack of standardization of clinical read-out measures, however, makes direct comparison of experimental therapies difficult. Damage and therapeutic effects in vivo are routinely evaluated using rather subjective behavioral tests. Here we show that manganese-enhanced magnetic resonance imaging (MEMRI) can be used to examine the extent of damage following spinal cord injury (SCI) in mice in vivo. Injection of MnCl2 solution into the cerebrospinal fluid leads to manganese uptake into the spinal cord. Furthermore, after injury MEMRI-derived quantitative measures correlate closely with clinical locomotor scores. Improved locomotion due to treating the detrimental effects of SCI with an established therapy (neutralization of CD95Ligand) is reflected in an increase of manganese uptake into the injured spinal cord. Therefore, we demonstrate that MEMRI is a sensitive and objective tool for in vivo visualization and quantification of damage and functional improvement after SCI. Thus, MEMRI can serve as a reproducible surrogate measure of the clinical status of the spinal cord in mice, potentially becoming a standard approach for evaluating experimental therapies. [less ▲]

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