Pascal Gelebart's research while affiliated with University of Bergen and other places
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Publications (57)
Background
Ovarian cancer (OC) is the leading cause of death from gynecologic malignancies in the Western world. Contributing factors include a high frequency of late-stage diagnosis, the development of chemoresistance, and the evasion of host immune responses. Currently, debulking surgery and platinum-based chemotherapy are the treatment cornersto...
Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma having a poor overall survival that is in need for the development of new therapeutics. In this study, we report the identification and expression of a new isoform splice variant of the tyrosine kinase receptor AXL in MCL cells. This new AXL isoform, called AXL3, lacks the liga...
Introduction/Background
Recently, ovarian cancer organoids have been developed, showing promising advantages compared to traditional 2D cell culture and mouse models. Organoids are 3D cell cultures and conventionally cancer cells are embedded in a gel composed of extracellular matrix (ECM) proteins. These gels do not fully mimic the native ECM of a...
The development of targeted and personalized therapies for cancer patients has underlined the need for more advanced preclinical animal models to facilitate and favor clinical translation. Patient-derived xenografts (PDXs) allow for the preservation of patient tumor architecture and intra-tumor heterogeneity and have emerged as a powerful tool in p...
Mantle cell lymphoma (MCL) is a non‐Hodgkin lymphoma that remains incurable with the treatment options available today. In the present study, we have identified the dihydroorotate dehydrogenase (DHODH), an essential enzyme for the de novo biosynthesis of pyrimidine‐based nucleotides, to be overexpressed in MCL in comparison to healthy peripheral bl...
We have previously shown that the Wnt canonical pathway (WCP) is constitutively active in most cases of mantle cell lymphoma (MCL). Here, we aimed to elucidate the mechanisms underlying this biochemical deregulation. We hypothesized that gene methylation/silencing of WIF1 (Wnt inhibitory factor-1), a physiologic inhibitor of WCP, contributes to the...
Endoplasmic reticulum (ER) calcium homeostasis plays an essential role in cellular calcium signaling, intra-ER protein chaperoning and maturation, as well as in the interaction of the ER with other organelles. Calcium is accumulated in the ER by sarco/endoplasmic reticulum calcium ATPases (SERCA enzymes) that generate by active, ATP-dependent trans...
B-cell receptor (BCR) signaling pathways and interactions with the tumor microenvironment account for mantle cell lymphoma (MCL) cells survival in lymphoid organs. In several MCL cases, the WNT/β-catenin canonical pathway is activated and β–catenin accumulates into the nucleus. As both BCR and β-catenin are important mediators of cell survival and...
The original PDF version of this Article listed the authors as “Marcus J.G.W. Ladds,” where it should have read “Marcus J. G. W. Ladds, Ingeborg M. M. van Leeuwen, Catherine J. Drummond et al.#”.
Also in the PDF version, it was incorrectly stated that “Correspondence and requests for materials should be addressed to S. Lín.”, instead of the correct...
The development of non-genotoxic therapies that activate wild-type p53 in tumors is of great interest since the discovery of p53 as a tumor suppressor. Here we report the identification of over 100 small-molecules activating p53 in cells. We elucidate the mechanism of action of a chiral tetrahydroindazole (HZ00), and through target deconvolution, w...
Despite the tremendous progress made in the comprehension of acute myeloid leukemia (AML) over the last 30 years most patients die from their disease. Our understanding of AML has relied on an intensive in-vitro research approach, based on AML cell lines as well as primary AML patient cells. However, experimental insight into the early events of AM...
The significance of loss of SOCS3, a negative regulator of signalling pathways including those of STAT3 and NF-κB, was examined in mantle cell lymphoma (MCL). The protein expression and gene methylation status of SOCS3 were detected using immunohistochemistry/Western blots and methylation-specific polymerase chain reaction, respectively. To evaluat...
The endoplasmic reticulum (ER) is a major intracellular calcium storage pool and a multifunctional organelle that accomplishes several calcium-dependent functions involved in many homeostatic and signaling mechanisms. Calcium is accumulated in the ER by Sarco/Endoplasmic Reticulum Calcium ATPase (SERCA)-type calcium pumps. SERCA activity can determ...
It was previously reported that β-catenin contributes to the tumorigenesis of ALK-positive anaplastic large cell lymphoma (ALK(+)ALCL), and the oncogenic effects of β-catenin in these tumors is promoted by NPM-ALK, an abnormal fusion protein characteristic of ALK(+)ALCL. In this study, we hypothesized that NPM-ALK promotes the oncogenic activity of...
Our previous oligonucleotide array studies revealed that ALK-positive anaplastic large cell lymphoma (ALK(+)ALCL) express high levels of the disheveled proteins (Dvls), a family of proteins that is integral to the Wnt signaling pathways. In this study, we assessed whether the Dvls are important in the pathogenesis of ALK(+)ALCL. By Western blotting...
Sox2 (sex-determining region Y-Box) is one of the master transcriptional factors that are important in maintaining the pluripotency of embryonic stem cells (ESCs). In line with this function, Sox2 expression is largely restricted to ESCs and somatic stem cells. We report that Sox2 is expressed in cell lines and tumor samples derived from ALK-positi...
SALL4 is one of the master transcriptional factors that are crucial in maintaining the pluripotency of embryonic stem cells (ESCs). While the expression of SALL4 is normally restricted to ESCs and somatic stem cells, we found that it is aberrantly expressed in ALK-positive anaplastic large cell lymphoma (ALK+ ALCL), a type of lymphoid malignancy ca...
Fatty acid synthase (FASN), a key player in the de novo synthetic pathway of long-chain fatty acids, has been shown to contribute to the tumorigenesis in various types of solid tumors. We here report that FASN is highly and consistently expressed in mantle cell lymphoma (MCL), an aggressive form of B-cell lymphoid malignancy. Specifically, the expr...
Downregulation of β-catenin with the use of two different siRNA sequences (labeled 1 and 2). Both siRNA species induced a dramatic decrease in FASN protein detectable by western blots. Two MCL cell lines, Jeko-1 (A) and Mino (B), were used for this experiment. Cell lysates were prepared 48 hours after the siRNA transfection.
(TIF)
The fusion tyrosine kinase NPM-ALK is central to the pathogenesis of ALK-positive anaplastic large cell lymphoma (ALK(+)ALCL). We recently identified that MSH2, a key DNA mismatch repair (MMR) protein integral to the suppression of tumorigenesis, is an NPM-ALK-interacting protein. In this study, we found in vitro evidence that enforced expression o...
Endoplasmic reticulum calcium homeostasis is involved in a multitude of signaling, as well as "house-keeping" functions that control cell growth, differentiation or apoptosis in every human/eukaryotic cell. Calcium is actively accumulated in the endoplasmic reticulum by Sarco/Endoplasmic Reticulum Calcium transport ATPases (SERCA enzymes). SERCA-de...
One of the main functions of A Disintegrin and Metalloproteinase 10 (ADAM10) is to regulate the bioavailability of adhesion molecules and ligands to various cellular-signaling receptors. Constitutive activation of ADAM10 has been implicated in the pathogenesis of several types of solid tumors. In this study, we found that mantle cell lymphoma (MCL)...
Mantle cell lymphoma (MCL) is a specific type of aggressive B-cell non-Hodgkin lymphoma. We recently found that IL-22RA1, one of the two subunits of the interleukin 22 (IL-22) receptor, is expressed in MCL cell lines but not benign lymphocytes. In view of normal functions of IL-22 signaling, we hypothesized that the aberrant expression of IL-22RA1...
Glycogen synthase kinase 3β (GSK-3β), recently found to be functionally abnormal in various types of human disease, is negatively regulated by the PI3K/Akt signaling pathway. Since Akt is constitutively activated in a subset of breast cancer, we hypothesized that GSK-3β is inappropriately inactivated in these cases. In this study, we aimed to asses...
The role of β-catenin in cancer has been most studied in tumors of epithelial cell origin. The functional status and biological significance of this protein in anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma is unknown.
ALK-positive anaplastic large cell lymphoma cell lines and patients' tumor samples were examined for stat...
The expression of β-catenin detectable by immunohistochemistry has been reported to be prognostically important in breast cancer. In this study, we investigated the mechanism by which β-catenin is regulated in breast cancer cells. Our analysis of the gene promoter of β-catenin revealed multiple putative STAT3 binding sites. In support of the concep...
The cytoplasmic tyrosine phosphatase SHP1 has been shown to inhibit the oncogenic fusion protein nucleophosmin (NPM)-anaplastic
lymphoma kinase (ALK), and loss of SHP1 contributes to NPM-ALK-mediated tumorigenesis. In this study, we aimed to further
understand how SHP1 interacts and regulates NPM-ALK. We employed an in vitro model in which GP293 ce...
GSK-3beta, a biologically important signalling protein, is regulated by the Wnt canonical and the PI3K/Akt pathways. We recently reported that mantle cell lymphoma (MCL) frequently shows evidence of GSK-3beta inactivation, since GSK-3beta is phoshorylated at its functionally critical serine 9 residue in all MCL cell lines and the majority of MCL tu...
Interleukin (IL)-21 has been reported to both stimulate cell growth and promote survival in benign lymphoid cells and several types of hematopoietic neoplasms. It induces JAK3/STAT3 signaling, a biologically important cellular pathway activated in most cases of anaplastic lymphoma kinase (ALK)-expressing anaplastic large cell lymphoma (ALK(+)ALCL)....
Aberrations of the Wnt canonical pathway (WCP) are known to contribute to the pathogenesis of various types of cancer. We hypothesize that these defects may exist in mantle cell lymphoma (MCL). Both the upstream and downstream aspects of WCP were examined in MCL cell lines and tumors. Using WCP-specific oligonucleotide arrays, we found that MCL hig...
One of the characteristic features of anaplastic lymphoma kinase (ALK)(+), anaplastic large cell lymphoma (ALK(+)ALCL) is the constitutive activation of signal transducers and activators of transcription-3 (STAT3), a defect believed to be important for the pathogenesis of these tumors. In this report, we describe the existence of an autocrine stimu...
Expression of ZAP-70 in chronic lymphocytic leukemia (CLL) predicts worse clinical outcome in patients with early-stage disease. It has become important to include ZAP-70 in the immunophenotyping panel used to diagnose CLL, commonly performed by flow cytometry (FC). Nevertheless, the methodology used to detect ZAP-70 by FC has not been extensively...
Context.—Expression of ZAP-70 in chronic lymphocytic leukemia (CLL) predicts worse clinical outcome in patients with early-stage disease. It has become important to include ZAP-70 in the immunophenotyping panel used to diagnose CLL, commonly performed by flow cytometry (FC). Nevertheless, the methodology used to detect ZAP-70 by FC has not been ext...
We recently documented the expression of a novel human mRNA variant encoding a yet uncharacterized SERCA [SR (sarcoplasmic reticulum)/ER (endoplasmic reticulum) Ca2+-ATPase] protein, SERCA2c [Gélébart, Martin, Enouf and Papp (2003) Biochem. Biophys. Res. Commun. 303, 676-684]. In the present study, we have analysed the expression and functional cha...
We uncovered a new pathway of interplay between calreticulin and myocyte-enhancer factor (MEF) 2C, a cardiac-specific transcription factor. We establish that calreticulin works upstream of calcineurin and MEF2C in a Ca(2+)-dependent signal transduction cascade that links the endoplasmic reticulum and the nucleus during cardiac development. In the a...
Calcium accumulation in the endoplasmic reticulum is accomplished by sarco/endoplasmic reticulum calcium transport ATPases (SERCA enzymes). To better characterize the role of SERCA3 in colon carcinogenesis, its expression has been investigated in colonic epithelium, benign lesions, adenomas, and adenocarcinomas. In addition, the regulation of SERCA...
Calreticulin is a 46-kDa Ca2+-binding chaperone found across a diverse range of species. The protein is involved in the regulation of intracellular Ca2+ homeostasis and endoplasmic reticulum (ER) Ca2+ storage capacity. Calreticulin is also an important molecular chaperone involved in "quality control" within secretory pathways. The protein contains...
The calcium homeostasis of the endoplasmic reticulum (ER) is connected to a multitude of cell functions involved in intracellular signal transduction, control of proliferation, programmed cell death, or the synthesis of mature proteins. Calcium is accumulated in the ER by various biochemically distinct sarco/endoplasmic reticulum calcium transport...
L’accumulation des ions calciques à partir du cytosol dans le reticulum endoplasmique (RE) est accomplie grâce à des ATPases calciques endoplasmiques (sarco/endoplasmic reticulum calcium transport ATPases – SERCA). Nous avons précédemment montré que l’expression de l’isoforme SERCA3 est perdue ou fortement réduite dans les cellules de cancer coliqu...
Sarco/endoplasmic reticulum-type calcium transport ATPases (SERCA enzymes) pump calcium ions from the cytosol into the endoplasmic reticulum. We report that in addition to the ubiquitously expressed SERCA2b isoform, a new splice variant of SERCA2 can be detected (SERCA2c) that arises from the inclusion of a short intronic sequence located between e...
Calcium mobilization from the endoplasmic reticulum (ER) into the cytosol is a key component of several signaling networks controlling tumor cell growth, differentiation, or apoptosis. Sarco/endoplasmic reticulum calcium transport ATPases (SERCA-type calcium pumps), enzymes that accumulate calcium in the ER, play an important role in these phenomen...
Sarco/endoplasmic reticulum Ca2+-ATPases (SERCAs) pump Ca2+ into the endoplasmic reticulum. Recently, three human SERCA3 (h3a-c) proteins and a previously unknown rat SERCA3 (r3b/c) mRNA have been described. Here, we (i) document two novel human SERCA3 splice variants h3d and h3e, (ii) provide data for the expression and mechanisms regulating the e...
Calcium is accumulated from the cytosol into the endoplasmic reticulum by sarco-endoplasmic reticulum calcium transport ATPase (SERCA) enzymes. Because calcium stored in the endoplasmic reticulum is essential for cell growth, differentiation, calcium signaling, and apoptosis and because different SERCA enzymes possess distinct functional characteri...
Calcium is accumulated from the cytosol into the endoplasmic reticulum by sarco-endoplasmic reticulum calcium transport ATPase (SERCA) enzymes. Because calcium stored in the endoplasmic reticulum is essential for cell growth, differentiation, calcium signaling, and apoptosis and because different SERCA enzymes possess distinct functional characteri...
Citations
... However, this strategy of using modified magnetic nanoparticles as carriers for p53 gene detection still has some limitations. The TP53 protein, also referred to as "the guardian of the genome," is crucial for the processes that repair a damaged genome [2,3]. According to the theory, it acts as a tumor suppressor and activates downstream genes that impede growth and/or invasion upon binding to a TP53-binding site. ...
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... Finally, AXL, a cell-surface receptor with an intrinsic tyrosine kinase activity, has been implicated in BCR-independent cell signaling (19) and drug resistance (20) in CLL/SLL. Of note, a recent study (21) reports that constitutively activated AXL3 variant is expressed in MCL and its inhibition has proven therapeutically effective in preclinical in vitro and in vivo models. ...
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... There are several methods to quantify ZAP-70 including: polymerase chain reaction (PCR), immunoblotting, immunohistochemistry, fluorescence in-situ hybridization (FISH) analysis and flow cytometry (Slack et al., 2007, Wang et al., 2012, Put et al., 2009, Vroblova et al., 2012, Matthews et al., 2004, Moreno and Montserrat, 2010. Use of flow cytometry for ZAP-70 detection seems to be advantageous as this technique enables us to assess the presence of ZAP-70 separately on CLL clone, T-cells and NK-cells. ...
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... During aging, damaged mitochondria produce less ATP, and more ROS accumulate [43]. The accumulation of ROS causes oxidative damage to macromolecules, including proteins. ...
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... The activation of Wnt/β-catenin signaling pathway can promote malignant phenotype of cancer (34,35). The Wnt/ β-catenin signaling pathway is involved in regulating the effect of drugs derived from natural products (36,37). ...
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... In particular, we observed early global genome perturbation in response to atRA [at 0-4 h: see Fig. 14 in Tsuchiya et al. (2020a)], which was not seen in the DMSO model. This may be due to a difference in Ca2+ influx (Papp et al. 2012), which controls key cell-fate processes including fertilization, early embryogenesis (Whitaker 2006), and differentiation (Yen et al. 1987;Schaefer et al. 1994;Dolmetsch et al. 1997;Launay et al. 1999). ...
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... Crystallization of DHODH with OSU-03012 and TAK-632 For co-crystallizaion of DHODH and OSU-03012, crystals were obtained using the same conditions reported in previously published DHODH structures Baumgartner et al., 2006;Das et al., 2013;Davies et al., 2009;Erra et al., 2011;Hurt et al., 2006;Ladds et al., 2018;Liu et al., 2000;McLean et al., 2010;Sainas et al., 2018;Walse et al., 2008), namely 1.6 -2.6 M ammonium sulfate and 5%-30% glycerol in the well in pH 4.5, with 20 mg/mL DHODH with 2 mM dihydroorotate (DHO), 20.8 mM dodecyldimethyl-Namineoxide (DDAO), and 400 mM inhibitor. Protein was mixed 1:1 with mother liquor and hanging drops were used at room temperature. ...
... As elaborated above, ETC function is required for de novo pyrimidine synthesis by sustaining DHODH activity. Consistent with this, DHODH inhibition has been shown to be efficacious in preclinical work across multiple tumor types (Sykes et al. 2016;Brown et al. 2017;Mathur et al. 2017;Koundinya et al. 2018;Ladds et al. 2018;Li et al. 2019). Similarly, the TCA cycle is integral to produce intermediate metabolites for growth and has been targeted for cancer therapy, most notably with CPI-613, which inhibits αketoglutarate dehydrogenase and pyruvate dehydrogenase (Pardee et al. 2014;Stuart et al. 2014;Alistar et al. 2016). ...
Reference: Mitochondria and Cancer
... Further evaluation of the efficacy towards AML cells, and perhaps equally important, the ability of nanoparticles to prevent off-target effects from CPZ on the central nervous system, should be done in an in vivo model. Using rodents like mice transplanted with human AML cells, it is possible to monitor development of the disease non-invasively using imaging techniques (Gelebart et al., 2015), and at the same time detect, for instance, changes in motor-effects caused by CPZ crossing the BBB. Importantly, it will also reveal to what extent our nanoparticles accumulate in the leukaemic bone marrow, which is the ultimate target for AML therapy. ...
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... The ATP2A3 genes produce SERCA pumps, which control the amount of Ca2 + in the cytosol and, thus, several cellular functions, including cell proliferation, differentiation, and apoptosis. Due to loss in the expression of the ATP2A3 gene results in disruption of calcium homeostasis, leading to increased cytosolic calcium levels resulting in the uncontrolled growth and reduced differentiation of cancer cells [48]. There have been several reports of ATP2A3 gene transcriptional down-regulation in gastric and colon cancer [49]. ...
