19 results on '"Kuipers TB"'
Search Results
2. BioIns-O-03 - Whole-genome profiling of primary cutaneous anaplastic large cell lymphoma.
- Author
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Tensen, CP, Torres, AN Bastidas, Melchers, RC, Van Grieken, L, Out-Luiting, J, Mei, H, Agaser, C, Kuipers, TB, Quint, KD, Willemze, R, Vermeer, MH, and Tensen, KEES
- Subjects
- *
CONFERENCES & conventions , *ANAPLASTIC large-cell lymphoma , *GENE expression profiling , *MULTIPLE tumors , *CUTANEOUS T-cell lymphoma - Published
- 2022
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3. PMP22 duplication dysregulates lipid homeostasis and plasma membrane organization in developing human Schwann cells.
- Author
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Prior R, Silva A, Vangansewinkel T, Idkowiak J, Tharkeshwar AK, Hellings TP, Michailidou I, Vreijling J, Loos M, Koopmans B, Vlek N, Agaser C, Kuipers TB, Michiels C, Rossaert E, Verschoren S, Vermeire W, de Laat V, Dehairs J, Eggermont K, van den Biggelaar D, Bademosi AT, Meunier FA, vandeVen M, Van Damme P, Mei H, Swinnen JV, Lambrichts I, Baas F, Fluiter K, Wolfs E, and Van Den Bosch L
- Subjects
- Humans, Animals, Mice, Sciatic Nerve metabolism, Gene Duplication, Schwann Cells metabolism, Myelin Proteins metabolism, Myelin Proteins genetics, Charcot-Marie-Tooth Disease genetics, Charcot-Marie-Tooth Disease metabolism, Charcot-Marie-Tooth Disease pathology, Homeostasis physiology, Lipid Metabolism physiology, Cell Membrane metabolism, Induced Pluripotent Stem Cells metabolism
- Abstract
Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited peripheral neuropathy caused by a 1.5 Mb tandem duplication of chromosome 17 harbouring the PMP22 gene. This dose-dependent overexpression of PMP22 results in disrupted Schwann cell myelination of peripheral nerves. To obtain better insights into the underlying pathogenic mechanisms in CMT1A, we investigated the role of PMP22 duplication in cellular homeostasis in CMT1A mouse models and in patient-derived induced pluripotent stem cells differentiated into Schwann cell precursors (iPSC-SCPs). We performed lipidomic profiling and bulk RNA sequencing (RNA-seq) on sciatic nerves of two developing CMT1A mouse models and on CMT1A patient-derived iPSC-SCPs. For the sciatic nerves of the CMT1A mice, cholesterol and lipid metabolism was downregulated in a dose-dependent manner throughout development. For the CMT1A iPSC-SCPs, transcriptional analysis unveiled a strong suppression of genes related to autophagy and lipid metabolism. Gene ontology enrichment analysis identified disturbances in pathways related to plasma membrane components and cell receptor signalling. Lipidomic analysis confirmed the severe dysregulation in plasma membrane lipids, particularly sphingolipids, in CMT1A iPSC-SCPs. Furthermore, we identified reduced lipid raft dynamics, disturbed plasma membrane fluidity and impaired cholesterol incorporation and storage, all of which could result from altered lipid storage homeostasis in the patient-derived CMT1A iPSC-SCPs. Importantly, this phenotype could be rescued by stimulating autophagy and lipolysis. We conclude that PMP22 duplication disturbs intracellular lipid storage and leads to a more disordered plasma membrane owing to an alteration in the lipid composition, which might ultimately lead to impaired axo-glial interactions. Moreover, targeting lipid handling and metabolism could hold promise for the treatment of patients with CMT1A., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)
- Published
- 2024
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4. Adults prenatally exposed to the Dutch Famine exhibit a metabolic signature associated with a broad spectrum of common diseases.
- Author
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Taeubert MJ, Kuipers TB, Zhou J, Li C, Wang S, Wang T, Tobi EW, Belsky DW, Lumey LH, and Heijmans BT
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- Humans, Female, Pregnancy, Middle Aged, Netherlands epidemiology, Male, Biomarkers blood, Diabetes Mellitus, Type 2 epidemiology, Diabetes Mellitus, Type 2 blood, Metabolomics, Metabolome, Metabolic Diseases epidemiology, Metabolic Diseases etiology, Magnetic Resonance Spectroscopy, Aged, World War II, Prenatal Exposure Delayed Effects, Famine
- Abstract
Background: Exposure to famine in the prenatal period is associated with an increased risk of metabolic disease, including obesity and type 2 diabetes. We employed nuclear magnetic resonance (NMR) metabolomic profiling to identify the metabolic changes that are associated with survival of prenatal famine exposure during the Dutch Famine at the end of World War II and subsequently assess their link to disease., Methods: NMR metabolomics data were generated from serum in 480 individuals prenatally exposed to famine (mean 58.8 years, 0.5 SD) and 464 controls (mean 57.9 years, 5.4 SD). We tested associations of prenatal famine exposure with levels of 168 individual metabolic biomarkers and compared the metabolic biomarker signature of famine exposure with those of 154 common diseases., Results: Prenatal famine exposure was associated with higher concentrations of branched-chain amino acids ((iso)-leucine), aromatic amino acid (tyrosine), and glucose in later life (0.2-0.3 SD, p < 3 × 10
-3 ). The metabolic biomarker signature of prenatal famine exposure was positively correlated to that of incident type 2 diabetes from the UK Biobank (r = 0.77, p = 3 × 10-27 ), also when re-estimating the signature of prenatal famine exposure among individuals without diabetes (r = 0.67, p = 1 × 10-18 ). Remarkably, this association extended to 115 common diseases for which signatures were available (0.3 ≤ r ≤ 0.9, p < 3.2 × 10-4 ). Correlations among metabolic signatures of famine exposure and disease outcomes were attenuated when the famine signature was adjusted for body mass index., Conclusions: Prenatal famine exposure is associated with a metabolic biomarker signature that strongly resembles signatures of a diverse set of diseases, an observation that can in part be attributed to a shared involvement of obesity., (© 2024. The Author(s).)- Published
- 2024
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5. Transcriptional and functional profiling identifies inflammation and endothelial-to-mesenchymal transition as potential drivers for phenotypic heterogeneity within a cohort of endothelial colony forming cells.
- Author
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Laan SNJ, de Boer S, Dirven RJ, van Moort I, Kuipers TB, Mei H, Bierings R, and Eikenboom J
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- Humans, Cells, Cultured, Endothelial Cells metabolism, Endothelial Cells pathology, Epithelial-Mesenchymal Transition, Cell Proliferation, Endothelial Progenitor Cells metabolism, Endothelial Progenitor Cells pathology, Male, Female, Middle Aged, Adult, Transcription, Genetic, Phenotype, Gene Expression Profiling, Cell Movement, Inflammation genetics, Transcriptome
- Abstract
Background: Endothelial colony-forming cells (ECFCs) derived from patients can be used to investigate pathogenic mechanisms of vascular diseases like von Willebrand disease. Considerable phenotypic heterogeneity has been observed between ECFC clones derived from healthy donors. This heterogeneity needs to be well understood in order to use ECFCs as endothelial models for disease., Objectives: Therefore, we aimed to determine phenotypic and gene expression differences between control ECFCs., Methods: A total of 34 ECFC clones derived from 16 healthy controls were analyzed. The transcriptome of a selection of ECFC clones (n = 15) was analyzed by bulk RNA sequencing and gene set enrichment analysis. Gene expression was measured in all ECFC clones by quantitative polymerase chain reaction. Phenotypic profiling was performed and migration speed of the ECFCs was measured using confocal microscopy, followed by automated quantification of cell morphometrics and migration speed., Results: Through hierarchical clustering of RNA expression profiles, we could distinguish 2 major clusters within the ECFC cohort. Major differences were associated with proliferation and migration in cluster 1 and inflammation and endothelial-to-mesenchymal transition in cluster 2. Phenotypic profiling showed significantly more and smaller ECFCs in cluster 1, which contained more and longer Weibel-Palade bodies. Migration speed in cluster 1 was also significantly higher., Conclusion: We observed a range of different RNA expression patterns between ECFC clones, mostly associated with inflammation and clear differences in Weibel-Palade body count and structure. We developed a quantitative polymerase chain reaction panel that can be used for the characterization of ECFC clones, which is essential for the correct analysis of pathogenic mechanisms in vascular disorders., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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6. Twisting the theory on the origin of human umbilical cord coiling featuring monozygotic twins.
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Todtenhaupt P, Kuipers TB, Dijkstra KL, Voortman LM, Franken LA, Spekman JA, Jonkman TH, Groene SG, Roest AA, Haak MC, Verweij ET, van Pel M, Lopriore E, Heijmans BT, and van der Meeren LE
- Subjects
- Humans, Female, Pregnancy, Transcriptome genetics, Fetal Development genetics, Fetal Development physiology, Male, Umbilical Cord, Twins, Monozygotic genetics, DNA Methylation genetics
- Abstract
The human umbilical cord (hUC) is the lifeline that connects the fetus to the mother. Hypercoiling of the hUC is associated with pre- and perinatal morbidity and mortality. We investigated the origin of hUC hypercoiling using state-of-the-art imaging and omics approaches. Macroscopic inspection of the hUC revealed the helices to originate from the arteries rather than other components of the hUC. Digital reconstruction of the hUC arteries showed the dynamic alignment of two layers of muscle fibers in the tunica media aligning in opposing directions. We observed that genetically identical twins can be discordant for hUC coiling, excluding genetic, many environmental, and parental origins of hUC coiling. Comparing the transcriptomic and DNA methylation profile of the hUC arteries of four twin pairs with discordant cord coiling, we detected 28 differentially expressed genes, but no differentially methylated CpGs. These genes play a role in vascular development, cell-cell interaction, and axis formation and may account for the increased number of hUC helices. When combined, our results provide a novel framework to understand the origin of hUC helices in fetal development., (© 2024 Todtenhaupt et al.)
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- 2024
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7. Causative mechanisms and clinical impact of immunoglobulin deficiencies in ataxia telangiectasia.
- Author
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Takada S, Weitering TJ, van Os NJH, Du L, Pico-Knijnenburg I, Kuipers TB, Mei H, Salzer E, Willemsen MAAP, Weemaes CMR, Pan-Hammarstrom Q, and van der Burg M
- Subjects
- Humans, Adult, Adolescent, Male, Female, Middle Aged, Child, Young Adult, Aged, Somatic Hypermutation, Immunoglobulin, Child, Preschool, Immunoglobulin A immunology, Immunoglobulin G immunology, Immunoglobulin G blood, Ataxia Telangiectasia immunology, Ataxia Telangiectasia genetics, Ataxia Telangiectasia Mutated Proteins deficiency, Ataxia Telangiectasia Mutated Proteins genetics, B-Lymphocytes immunology, Immunoglobulin Class Switching
- Abstract
Background: Ataxia telangiectasia (AT) is characterized by cerebellar ataxia, telangiectasia, immunodeficiency, and increased cancer susceptibility and is caused by mutations in the ataxia telangiectasia mutated (ATM) gene. The immunodeficiency comprises predominantly immunoglobulin deficiency, mainly IgA and IgG
2 , with a variable severity. So far, the exact mechanisms underlying the immunoglobulin deficiency, especially the variable severity, remain unelucidated., Objective: We characterized the clinical impact of immunoglobulin deficiencies in AT and elucidated their mechanisms in AT., Methods: We analyzed long-term immunoglobulin levels, immunophenotyping, and survival time in our cohort (n = 87, median age 16 years; maximum 64 years). Somatic hypermutation and class-switch junctions in B cells were analyzed by next-generation sequencing. Furthermore, an in vitro class-switching induction assay was performed, followed by RNA sequencing, to assess the effect of ATM inhibition., Results: Only the hyper-IgM AT phenotype significantly worsened survival time, while IgA or IgG2 deficiencies did not. The immunoglobulin levels showed predominantly decreased IgG2 and IgA. Moreover, flow cytometric analysis demonstrated reduced naive B and T lymphocytes and a deficiency of class-switched IgG2 and IgA memory B cells. Somatic hypermutation frequencies were lowered in IgA- and IgG2 -deficient patients, indicating hampered germinal center reaction. In addition, the microhomology of switch junctions was elongated, suggesting alternative end joining during class-switch DNA repair. The in vitro class switching and proliferation were negatively affected by ATM inhibition. RNA sequencing analysis showed that ATM inhibitor influenced expression of germinal center reaction genes., Conclusion: Immunoglobulin deficiency in AT is caused by disturbed development of class-switched memory B cells. ATM deficiency affects both germinal center reaction and choice of DNA-repair pathway in class switching., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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8. Transcriptomic profiling of Polycystic Kidney Disease identifies paracrine factors in the early cyst microenvironment.
- Author
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Yasinoglu SA, Kuipers TB, Suidgeest E, van der Weerd L, Mei H, Baelde HJ, and Peters DJM
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- Mice, Animals, Kidney metabolism, Gene Expression Profiling, Tumor Microenvironment, Polycystic Kidney Diseases genetics, Polycystic Kidney Diseases metabolism, Cysts genetics
- Abstract
Initial cysts that are formed upon Pkd1 loss in mice impose persistent stress on surrounding tissue and trigger a cystic snowball effect, in which local aberrant PKD-related signaling increases the likelihood of new cyst formation, ultimately leading to accelerated disease progression. Although many pathways have been associated with PKD progression, the knowledge of early changes near initial cysts is limited. To perform an unbiased analysis of transcriptomic alterations in the cyst microenvironment, microdomains were collected from kidney sections of iKsp-Pkd1
del mice with scattered Pkd1-deletion using Laser Capture Microdissection. These microdomains were defined as F4/80-low cystic, representing early alterations in the cyst microenvironment, F4/80-high cystic, with more advanced alterations, or non-cystic. RNA sequencing and differential gene expression analysis revealed 953 and 8088 dysregulated genes in the F4/80-low and F4/80-high cyst microenvironment, respectively, when compared to non-cystic microdomains. In the early cyst microenvironment, several injury-repair, growth, and tissue remodeling-related pathways were activated, accompanied by mild metabolic changes. In the more advanced F4/80-high microdomains, these pathways were potentiated and the metabolism was highly dysregulated. Upstream regulator analysis revealed a series of paracrine factors with increased activity in the early cyst microenvironment, including TNFSF12 and OSM. In line with the upstream regulator analysis, TWEAK and Oncostatin-M promoted cell proliferation and inflammatory gene expression in renal epithelial cells and fibroblasts in vitro. Collectively, our data provide an overview of molecular alterations that specifically occur in the cyst microenvironment and identify paracrine factors that may mediate early and advanced alterations in the cyst microenvironment., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: D.J.M. Peters reports financial support was provided by Dutch Kidney Foundation. D.J.M. Peters reports a relationship with Mironid Ltd. that includes: consulting or advisory. D.J.M. Peters reports a relationship with Crown Bioscience Inc. that includes: consulting or advisory. D.J.M. Peters reports a relationship with Innoser Laboratories BV that includes: consulting or advisory., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2024
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9. RNA-sequencing to discover genes and signaling pathways associated with venous thromboembolism in glioblastoma patients: A case-control study.
- Author
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Kapteijn MY, Lanting VR, Kaptein FHJ, Guman NAM, Laghmani EH, Kuipers TB, Mei H, Goeman JJ, Mulder FI, van Duinen SG, Taphoorn MJB, Dirven L, Broekman MLD, van Es N, Klok FA, Koekkoek JAF, Versteeg HH, and Buijs JT
- Subjects
- Humans, Case-Control Studies, Hedgehog Proteins genetics, Hedgehog Proteins metabolism, Signal Transduction genetics, RNA, Venous Thromboembolism genetics, Glioblastoma complications, Glioblastoma genetics, Glioblastoma pathology
- Abstract
Background: Glioblastoma patients are at high risk of developing venous thromboembolism (VTE). Tumor-intrinsic features are considered to play a role, but the underlying pathophysiological mechanisms remain incompletely understood., Objectives: To identify tumor-expressed genes and signaling pathways that associate with glioblastoma-related VTE by using next generation RNA-sequencing (RNA-Seq)., Methods: The tumor gene expression profile of 23 glioblastoma patients with VTE and 23 glioblastoma patients without VTE was compared using an unpaired analysis. Ingenuity Pathway Analysis (IPA) core analysis was performed on the top 50 differentially expressed genes to explore associated functions and pathways. Based on full RNA-Seq data, molecular glioblastoma subtypes were determined by performing cluster analysis., Results: Of the 19,327 genes, 1246 (6.4 %) were differentially expressed between glioblastoma patients with and without VTE (unadjusted P < 0.05). The most highly overexpressed gene was GLI1, a classical target gene in the Sonic Hedgehog (Shh) signaling pathway (log2 fold change: 3.7; unadjusted P < 0.0001, adjusted P = 0.219). In line, Shh signaling was among the top canonical pathways and processes associated with VTE. The proportion of patients with the proneural/neural glioblastoma subtype was higher among those with VTE than controls., Conclusion: Shh signaling may be involved in the development of glioblastoma-related VTE., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: F.A.K. has received research support from Bayer, BMS, BSCI, MSD, Leo Pharma, Actelion, Farm-X, The Netherlands Organization for Health Research and Development, The Dutch Thrombosis Foundation, The Dutch Heart Foundation and the Horizon Europe Program, all paid to his institution and outside the submitted work. The other authors have no conflicts of interest to declare., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2023
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10. Genetic analysis of selection bias in a natural experiment: Investigating in-utero famine effects on elevated body mass index in the Dutch Hunger Winter Families Study.
- Author
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Zhou J, Indik CE, Kuipers TB, Li C, Nivard MG, Ryan CP, Tucker-Drob EM, Taeubert MJ, Wang S, Wang T, Conley D, Heijmans BT, Lumey LH, and Belsky DW
- Abstract
Natural-experiment designs that compare survivors of in-utero famine exposure to unaffected controls suggest that in-utero undernutrition predisposes to development of obesity. However, birth rates drop dramatically during famines. Selection bias could arise if factors that contribute to obesity also protect fertility and/or fetal survival under famine conditions. We investigated this hypothesis using genetic analysis of a famine-exposed birth cohort. We genotyped participants in the Dutch Hunger Winter Families Study (DHWFS, N=950; 45% male), of whom 51% were exposed to the 1944-1945 Dutch Famine during gestation and 49% were their unexposed same-sex siblings or "time controls" born before or after the famine in the same hospitals. We computed body-mass index (BMI) polygenic indices (PGIs) in DHWFS participants and compared BMI PGIs between famine-exposed and control groups. Participants with higher polygenic risk had higher BMIs (Pearson r=0.42, p<0.001). However, differences between BMI PGIs of famine-exposed participants and controls were small and not statistically different from zero across specifications (Cohen's d=0.10, p>0.092). Our findings did not indicate selection bias, supporting the validity of the natural-experiment design within DHWFS. In summary, our study outlines a novel approach to explore the presence of selection bias in famine and other natural experiment studies.
- Published
- 2023
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11. Short salsalate administration affects cell proliferation, metabolism, and inflammation in polycystic kidney disease.
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Kanhai AA, Sánchez-López E, Kuipers TB, van Klinken JB, Dijkstra KL, van der Veen I, Baelde HJ, Song X, Pei Y, Mei H, Leonhard WN, Mayboroda OA, and Peters DJM
- Abstract
Metabolic reprogramming is a driver of autosomal dominant polycystic kidney disease (ADPKD) progression and a potential therapeutic intervention route. We showed before that the AMP-associated protein kinase (AMPK) activator salsalate attenuates cystic disease progression. Here, we aim to study the early, direct effects of short salsalate treatment in adult-onset conditional Pkd1 deletion mice. Cystic mice were treated with salsalate for two weeks, after which NMR metabolomics and RNA sequencing analyses were performed. Pkd1 deletion resulted in clear metabolomic dysregulation. Short salsalate treatment has small, but significant, effects, reverting acetylcarnitine and phosphocholine concentrations back to wildtype levels, and showing associations with altered purine metabolism. RNA sequencing revealed that short salsalate treatment, next to restoring energy metabolism toward wildtype levels, also affects cell proliferation and inflammation, in PKD. We show that salsalate positively affects major dysregulated processes in ADPKD: energy metabolism, cell proliferation, and inflammation, providing more insights into its working mechanisms., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)
- Published
- 2023
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12. The lncRNA LETS1 promotes TGF-β-induced EMT and cancer cell migration by transcriptionally activating a TβR1-stabilizing mechanism.
- Author
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Fan C, González-Prieto R, Kuipers TB, Vertegaal ACO, van Veelen PA, Mei H, and Ten Dijke P
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- Animals, Humans, Transforming Growth Factor beta metabolism, Zebrafish genetics, Zebrafish metabolism, Receptors, Transforming Growth Factor beta genetics, Cell Movement genetics, RNA, Long Noncoding genetics, RNA, Long Noncoding metabolism, Neoplasms
- Abstract
Transforming growth factor-β (TGF-β) signaling is a critical driver of epithelial-to-mesenchymal transition (EMT) and cancer progression. In SMAD-dependent TGF-β signaling, activation of the TGF-β receptor complex stimulates the phosphorylation of the intracellular receptor-associated SMADs (SMAD2 and SMAD3), which translocate to the nucleus to promote target gene expression. SMAD7 inhibits signaling through the pathway by promoting the polyubiquitination of the TGF-β type I receptor (TβRI). We identified an unannotated nuclear long noncoding RNA (lncRNA) that we designated LETS1 (lncRNA enforcing TGF-β signaling 1) that was not only increased but also perpetuated by TGF-β signaling. Loss of LETS1 attenuated TGF-β-induced EMT and migration in breast and lung cancer cells in vitro and extravasation of the cells in a zebrafish xenograft model. LETS1 potentiated TGF-β-SMAD signaling by stabilizing cell surface TβRI, thereby forming a positive feedback loop. Specifically, LETS1 inhibited TβRI polyubiquitination by binding to nuclear factor of activated T cells (NFAT5) and inducing the expression of the gene encoding the orphan nuclear receptor 4A1 (NR4A1), a component of a destruction complex for SMAD7. Overall, our findings characterize LETS1 as an EMT-promoting lncRNA that potentiates signaling through TGF-β receptor complexes.
- Published
- 2023
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13. Differential optineurin expression controls TGFβ signaling and is a key determinant for metastasis of triple negative breast cancer.
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Liu S, van Dinther M, Hagenaars SC, Gu Y, Kuipers TB, Mei H, Gomez-Puerto MC, Mesker WE, and Ten Dijke P
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- Humans, Cell Line, Tumor, Neoplasm Metastasis, Neoplasm Recurrence, Local, RNA, Messenger genetics, Transforming Growth Factor beta genetics, Transforming Growth Factor beta metabolism, Triple Negative Breast Neoplasms pathology, Cell Cycle Proteins metabolism, Membrane Transport Proteins metabolism
- Abstract
Triple-negative breast cancer (TNBC) is the most challenging breast cancer subtype to treat due to its aggressive characteristics and low response to the existing clinical therapies. Distant metastasis is the main cause of death of TNBC patients. Better understanding of the mechanisms underlying TNBC metastasis may lead to new strategies of early diagnosis and more efficient treatment. In our study, we uncovered that the autophagy receptor optineurin (OPTN) plays an unexpected role in TNBC metastasis. Data mining of publicly available data bases revealed that the mRNA level of OPTN in TNBC patients positively correlates with relapse free and distance metastasis free survival. Importantly, in vitro and in vivo models demonstrated that OPTN suppresses TNBC metastasis. Mechanistically, OPTN inhibited the pro-oncogenic transforming growth factor-β (TGFβ) signaling in TNBC cells by interacting with TGFβ type I receptor (TβRI) and promoting its ubiquitination for degradation. Consistent with our experimental findings, the clinical TNBC samples displayed a negative correlation between OPTN mRNA expression and TGFβ gene response signature and expression of proto-typic TGFβ target genes. Altogether, our study demonstrates that OPTN is a negative regulator for TGFβ receptor/SMAD signaling and suppresses metastasis in TNBC., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)
- Published
- 2023
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14. LncRNA LITATS1 suppresses TGF-β-induced EMT and cancer cell plasticity by potentiating TβRI degradation.
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Fan C, Wang Q, Kuipers TB, Cats D, Iyengar PV, Hagenaars SC, Mesker WE, Devilee P, Tollenaar RAEM, Mei H, and Ten Dijke P
- Subjects
- Humans, Cell Line, Tumor, Cell Movement, Cell Plasticity, Epithelial-Mesenchymal Transition genetics, Transforming Growth Factor beta metabolism, Ubiquitin-Protein Ligases genetics, Receptor, Transforming Growth Factor-beta Type I, Carcinoma, Non-Small-Cell Lung metabolism, Lung Neoplasms metabolism, RNA, Long Noncoding genetics
- Abstract
Epithelial cells acquire mesenchymal phenotypes through epithelial-mesenchymal transition (EMT) during cancer progression. However, how epithelial cells retain their epithelial traits and prevent malignant transformation is not well understood. Here, we report that the long noncoding RNA LITATS1 (LINC01137, ZC3H12A-DT) is an epithelial gatekeeper in normal epithelial cells and inhibits EMT in breast and non-small cell lung cancer cells. Transcriptome analysis identified LITATS1 as a TGF-β target gene. LITATS1 expression is reduced in lung adenocarcinoma tissues compared with adjacent normal tissues and correlates with a favorable prognosis in breast and non-small cell lung cancer patients. LITATS1 depletion promotes TGF-β-induced EMT, migration, and extravasation in cancer cells. Unbiased pathway analysis demonstrated that LITATS1 knockdown potently and selectively potentiates TGF-β/SMAD signaling. Mechanistically, LITATS1 enhances the polyubiquitination and proteasomal degradation of TGF-β type I receptor (TβRI). LITATS1 interacts with TβRI and the E3 ligase SMURF2, promoting the cytoplasmic retention of SMURF2. Our findings highlight a protective function of LITATS1 in epithelial integrity maintenance through the attenuation of TGF-β/SMAD signaling and EMT., (© 2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)
- Published
- 2023
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15. The systemic inhibition of the terminal complement system reduces neuroinflammation but does not improve motor function in mouse models of CMT1A with overexpressed PMP22 .
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Michailidou I, Vreijling J, Rumpf M, Loos M, Koopmans B, Vlek N, Straat N, Agaser C, Kuipers TB, Mei H, Baas F, and Fluiter K
- Abstract
Charcot-Marie-Tooth disease type 1A (CMT1A) is the most prevalent hereditary demyelinating neuropathy. This autosomal, dominantly inherited disease is caused by a duplication on chromosome 17p which includes the peripheral myelin protein 22 (PMP22) gene. There is clinical evidence that the disability in CMT1A is to a large extend due to axonal damage rather than demyelination. Over-expression of PMP22 is recently thought to impede cholesterol trafficking causing a total shutdown of local cholesterol and lipid synthesis in the Schwann cells, thus disturbing their ability to remyelinate. But there is a large variety in disease burden between CMT1A patients with the same genetic defect, indicating the presence of modifying factors that affect disease severity. One of these potential factors is the immune system. Several reports have described patients with co-occurrence of CMT1A with chronic inflammatory demyelinating disease or Guillain-Barré syndrome. We have previously shown in multiple animal models that the innate immune system and specifically the terminal complement system is a driver of inflammatory demyelination. To test the contribution of the terminal complement system to neuroinflammation and disease progression in CMT1A, we inhibited systemic complement C6 in two transgenic mouse models for CMT1A, the C3- PMP22 and C3- PMP22 c-JunP0Cre models. Both models over-express human PMP22 , and one (C3- PMP22 c-JunP0Cre) also has a Schwann cell-specific knockout of c-Jun, a crucial regulator of myelination controlling autophagy. We found that systemic inhibition of C6 using antisense oligonucleotides affects the neuroinflammation, Rho GTPase and ERK/MAPK signalling pathways in the CMT1A mouse models. The cholesterol synthesis pathway remained unaffected. Analysis of motor function during treatment with C6 antisense oligonucleotides did not reveal any significant improvement in the CMT1A mouse models. This study shows that the contribution of the terminal complement system to progressive loss of motor function in the CMT1A mouse models tested is limited., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Frank Baas reports a relationship with Complement Pharma BV that includes: board membership. Kees Fluiter reports a relationship with Complement Pharma BV that includes: consulting or advisory. Maarten Loos reports a relationship with Synaptologics BV that includes: employment. Bastijn Koopmans reports a relationship with Synaptologics BV that includes: employment. Nina Vlek reports a relationship with Synaptologics BV that includes: employment. Nina Straat reports a relationship with Synaptologics BV that includes: employment. Frank Baas has patent Complement inhibition for improved nerve regeneration issued to Regenesance BV. Frank Baas has patent COMPLEMENT ANTAGONISTS AND USES THEREOF issued to Regenesance BV. Kees Fluiter has patent COMPLEMENT ANTAGONISTS AND USES THEREOF issued to Regenesance BV. Frank Baas has patent #ANTIBODIES THAT BIND HUMAN C6 AND USES THEREOF issued to Regenesance BV., (© 2023 The Authors.)
- Published
- 2023
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16. Development, Characterization, and in vivo Validation of a Humanized C6 Monoclonal Antibody that Inhibits the Membrane Attack Complex.
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Gytz Olesen H, Michailidou I, Zelek WM, Vreijling J, Ruizendaal P, de Klein F, Marquart JA, Kuipers TB, Mei H, Zhang Y, Ahasan M, Johnson KK, Wang Y, Morgan BP, van Dijk M, Fluiter K, Andersen GR, and Baas F
- Subjects
- Rats, Animals, Humans, Rats, Transgenic, Complement C6, Antibodies, Monoclonal therapeutic use, Complement Membrane Attack Complex chemistry, Complement Membrane Attack Complex metabolism, Complement System Proteins
- Abstract
Damage and disease of nerves activates the complement system. We demonstrated that activation of the terminal pathway of the complement system leads to the formation of the membrane attack complex (MAC) and delays regeneration in the peripheral nervous system. Animals deficient in the complement component C6 showed improved recovery after neuronal trauma. Thus, inhibitors of the MAC might be of therapeutic use in neurological disease. Here, we describe the development, structure, mode of action, and properties of a novel therapeutic monoclonal antibody, CP010, against C6 that prevents formation of the MAC in vivo. The monoclonal antibody is humanized and specific for C6 and binds to an epitope in the FIM1-2 domain of human and primate C6 with sub-nanomolar affinity. Using biophysical and structural studies, we show that the anti-C6 antibody prevents the interaction between C6 and C5/C5b by blocking the C6 FIM1-2:C5 C345c axis. Systemic administration of the anti-C6 mAb caused complete depletion of free C6 in circulation in transgenic rats expressing human C6 and thereby inhibited MAC formation. The antibody prevented disease in experimental autoimmune myasthenia gravis and ameliorated relapse in chronic relapsing experimental autoimmune encephalomyelitis in human C6 transgenic rats. CP010 is a promising complement C6 inhibitor that prevents MAC formation. Systemic administration of this C6 monoclonal antibody has therapeutic potential in the treatment of neuronal disease., (© 2022 The Author(s). Published by S. Karger AG, Basel.)
- Published
- 2023
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17. Characterizing the secretome of licensed hiPSC-derived MSCs.
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Ramos YFM, Tertel T, Shaw G, Staubach S, de Almeida RC, Suchiman E, Kuipers TB, Mei H, Barry F, Murphy M, Giebel B, and Meulenbelt I
- Subjects
- Cell- and Tissue-Based Therapy, Humans, Secretome, Extracellular Vesicles metabolism, Induced Pluripotent Stem Cells metabolism, Mesenchymal Stem Cells metabolism
- Abstract
Although mesenchymal stromal cells (MSCs) from primary tissues have been successfully applied in the clinic, their expansion capabilities are limited and results are variable. MSCs derived from human-induced pluripotent stem cells (hiMSCs) are expected to overcome these limitations and serve as a reproducible and sustainable cell source. We have explored characteristics and therapeutic potential of hiMSCs in comparison to hBMSCs. RNA sequencing confirmed high resemblance, with average Pearson correlation of 0.88 and Jaccard similarity index of 0.99, and similar to hBMSCs the hiMSCs released extracellular vesicles with in vitro immunomodulatory properties. Potency assay with TNFα and IFNγ demonstrated an increase in well-known immunomodulatory genes such as IDO1, CXCL8/IL8, and HLA-DRA which was also highlighted by enhanced secretion in the media. Notably, expression of 125 genes increased more than 1000-fold. These genes were predicted to be regulated by NFΚB signaling, known to play a central role in immune response. Altogether, our data qualify hiMSCs as a promising source for cell therapy and/or cell-based therapeutic products. Additionally, the herewith generated database will add to our understanding of the mode of action of regenerative cell-based therapies and could be used to identify relevant potency markers., (© 2022. The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
18. Whole-genome profiling of primary cutaneous anaplastic large cell lymphoma.
- Author
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Bastidas Torres AN, Melchers RC, Van Grieken L, Out-Luiting JJ, Mei H, Agaser C, Kuipers TB, Quint KD, Willemze R, Vermeer MH, and Tensen CP
- Subjects
- 3-Phosphoinositide-Dependent Protein Kinases, Fetal Proteins, Humans, Ki-1 Antigen, Protein-Tyrosine Kinases, Proto-Oncogene Proteins c-akt, Lymphoma, Large-Cell, Anaplastic genetics, Lymphoma, Large-Cell, Anaplastic pathology, Lymphoma, Primary Cutaneous Anaplastic Large Cell, Lymphoproliferative Disorders pathology, Skin Neoplasms metabolism
- Abstract
Primary cutaneous anaplastic large cell lymphoma (pcALCL), a hematological neoplasm caused by skin-homing CD30+ malignant T cells, is part of the spectrum of primary cutaneous CD30+ lymphoproliferative disorders. To date, only a small number of molecular alterations have been described in pcALCL and, so far, no clear unifying theme that could explain the pathogenetic origin of the disease has emerged among patients. In order to clarify the pathogenetic basis of pcALCL, we performed high-resolution genetic profiling (genome/transcriptome) of this lymphoma (n=12) by using whole-genome sequencing, whole-exome sequencing and RNA sequencing. Our study, which uncovered novel genomic rearrangements, copy number alterations and small-scale mutations underlying this malignancy, revealed that the cell cycle, T-cell physiology regulation, transcription and signaling via the PI-3-K, MAPK and G-protein pathways are cellular processes commonly impacted by molecular alterations in patients with pcALCL. Recurrent events affecting cancer-associated genes included deletion of PRDM1 and TNFRSF14, gain of EZH2 and TNFRSF8, small-scale mutations in LRP1B, PDPK1 and PIK3R1 and rearrangements involving GPS2, LINC-PINT and TNK1. Consistent with the genomic data, transcriptome analysis uncovered upregulation of signal transduction routes associated with the PI-3-K, MAPK and G-protein pathways (e.g., ERK, phospholipase C, AKT). Our molecular findings suggest that inhibition of proliferation-promoting pathways altered in pcALCL (particularly PI-3-K/AKT signaling) should be explored as potential alternative therapy for patients with this lymphoma, especially, for cases that do not respond to first-line skin-directed therapies or with extracutaneous disease.
- Published
- 2022
- Full Text
- View/download PDF
19. Improved Sézary cell detection and novel insights into immunophenotypic and molecular heterogeneity in Sézary syndrome.
- Author
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Najidh S, Tensen CP, van der Sluijs-Gelling AJ, Teodosio C, Cats D, Mei H, Kuipers TB, Out-Luijting JJ, Zoutman WH, van Hall T, Orfao A, Almeida J, van Dongen JJM, and Vermeer MH
- Subjects
- Aged, Aged, 80 and over, Antigens, CD analysis, Female, Flow Cytometry, Humans, Immunophenotyping, Lymphocytes pathology, Male, Middle Aged, Prospective Studies, Sezary Syndrome pathology, Skin Neoplasms pathology, Sezary Syndrome diagnosis, Skin Neoplasms diagnosis
- Abstract
Sézary syndrome (SS) is an aggressive leukemic form of cutaneous T-cell lymphoma with neoplastic CD4+ T cells present in skin, lymph nodes, and blood. Despite advances in therapy, prognosis remains poor, with a 5-year overall survival of 30%. The immunophenotype of Sézary cells is diverse, which hampers efficient diagnosis, sensitive disease monitoring, and accurate assessment of treatment response. Comprehensive immunophenotypic profiling of Sézary cells with an in-depth analysis of maturation and functional subsets has not been performed thus far. We immunophenotypically profiled 24 patients with SS using standardized and sensitive EuroFlow-based multiparameter flow cytometry. We accurately identified and quantified Sézary cells in blood and performed an in-depth assessment of their phenotypic characteristics in comparison with their normal counterparts in the blood CD4+ T-cell compartment. We observed inter- and intrapatient heterogeneity and phenotypic changes over time. Sézary cells exhibited phenotypes corresponding with classical and nonclassical T helper subsets with different maturation phenotypes. We combined multiparameter flow cytometry analyses with fluorescence-activated cell sorting and performed RNA sequencing studies on purified subsets of malignant Sézary cells and normal CD4+ T cells of the same patients. We confirmed pure monoclonality in Sézary subsets, compared transcriptomes of phenotypically distinct Sézary subsets, and identified novel downregulated genes, most remarkably THEMIS and LAIR1, which discriminate Sézary cells from normal residual CD4+ T cells. Together, these findings further unravel the heterogeneity of Sézary cell subpopulations within and between patients. These new data will support improved blood staging and more accurate disease monitoring., (© 2021 by The American Society of Hematology.)
- Published
- 2021
- Full Text
- View/download PDF
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