| 1. |
- Akbari, Parsa, et al.
(author)
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Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity
- 2021
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In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 373:6550
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Journal article (peer-reviewed)abstract
- Large-scale human exome sequencing can identify rare protein-coding variants with a large impact on complex traits such as body adiposity. We sequenced the exomes of 645,626 individuals from the United Kingdom, the United States, and Mexico and estimated associations of rare coding variants with body mass index (BMI). We identified 16 genes with an exome-wide significant association with BMI, including those encoding five brain-expressed G protein-coupled receptors (CALCR, MC4R, GIPR, GPR151, and GPR75). Protein-truncating variants in GPR75 were observed in ∼4/10,000 sequenced individuals and were associated with 1.8 kilograms per square meter lower BMI and 54% lower odds of obesity in the heterozygous state. Knock out of Gpr75 in mice resulted in resistance to weight gain and improved glycemic control in a high-fat diet model. Inhibition of GPR75 may provide a therapeutic strategy for obesity.
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| 2. |
- Hippe, Andreas, et al.
(author)
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EGFR/Ras-induced CCL20 production modulates the tumour microenvironment.
- 2020
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In: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 123:6, s. 942-954
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Journal article (peer-reviewed)abstract
- BACKGROUND: The activation of the EGFR/Ras-signalling pathway in tumour cells induces a distinct chemokine repertoire, which in turn modulates the tumour microenvironment.METHODS: The effects of EGFR/Ras on the expression and translation of CCL20 were analysed in a large set of epithelial cancer cell lines and tumour tissues by RT-qPCR and ELISA in vitro. CCL20 production was verified by immunohistochemistry in different tumour tissues and correlated with clinical data. The effects of CCL20 on endothelial cell migration and tumour-associated vascularisation were comprehensively analysed with chemotaxis assays in vitro and in CCR6-deficient mice in vivo.RESULTS: Tumours facilitate progression by the EGFR/Ras-induced production of CCL20. Expression of the chemokine CCL20 in tumours correlates with advanced tumour stage, increased lymph node metastasis and decreased survival in patients. Microvascular endothelial cells abundantly express the specific CCL20 receptor CCR6. CCR6 signalling in endothelial cells induces angiogenesis. CCR6-deficient mice show significantly decreased tumour growth and tumour-associated vascularisation. The observed phenotype is dependent on CCR6 deficiency in stromal cells but not within the immune system.CONCLUSION: We propose that the chemokine axis CCL20-CCR6 represents a novel and promising target to interfere with the tumour microenvironment, and opens an innovative multimodal strategy for cancer therapy.
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| 3. |
- Kolliopoulos, Constantinos
(author)
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Role of TGFβ-induced hyaluronan-CD44 signaling in cancer progression
- 2021
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Doctoral thesis (other academic/artistic)abstract
- Hyaluronan, a prevalent glycosaminoglycan of the extracellular space often accumulates in pathological conditions, such as chronic inflammation, infection, and cancer. Hyaluronan synthase HAS2 has been responsible for the synthesis and deposition of hyaluronan in a variety of tumors. We have shown that HAS2 was required for efficient transforming growth factor β (TGFβ)-induced epithelial to mesenchymal transition (EMT), a developmental program which is commandeered by cancer cells to increase their migratory and invasive capacity. In study I, our findings show that long non-coding RNA Has2as has a key role in TGFβ- and Has2-induced breast cancer EMT, migration and acquisition of stemness.Hyaluronan conveys its signaling properties via binding to its cell surface receptor CD44, a well-established stem cell marker in a plethora of tumors. CD44 exerts its signaling properties by interacting with components of the actin cytoskeleton machinery, and by acting as a co-receptor for other receptor tyrosine or threonine kinases impacting their signaling properties. Furthermore, CD44 is subjected to proteolytic cleavage, which eventually liberates the cytoplasmic tail (CD44-ICD). CD44-ICD translocates to the nucleus and alters gene expression. In study II, our findings support that TRAF4/6 mediates pro-tumorigenic effects of CD44, and suggests that inhibitors of CD44 signaling via TRAF4/6 and RAC1 may be beneficial in the treatment of tumor patients.Glioblastoma (GBM) multiforme remains one of the most aggressive and lethal types of brain tumors worldwide with a poor prognosis. In study III, we have initiated studies to elucidate the CD44-dependent molecular mechanisms in GBM progression by knocking out (KO) CD44 by employing CRISPR/Cas9 gene editing in glioma U251MG cells.Aberrant hyaluronan levels are also found during infectious diseases. In study V, we show that in a cohort study of dengue patients, high levels of circulating Dengue Nonstructural Protein 1 (NS1) correlate with high levels of serum hyaluronan. Moreover, we propose that hyaluronan can serve as a prognostic marker for the onset of warning signs during the course of dengue viral infection. Mechanistically, NS1 treatment-induced hyaluronan production contributing to increased vascular permeability.In study IV, we have identified a bifurcating loop during TGFβ signaling, whereby transcriptional induction of NUAK1 serves as a negative checkpoint and NUAK2 induction positively contributes to signaling and terminal differentiation responses to TGFβ activity.In summary, the current thesis provides mechanistic insights into the roles of TGFβ-induced hyaluronan-CD44 interactions in cancer progression.
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| 4. |
- Verweij, Niek, et al.
(author)
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Germline Mutations in CIDEB and Protection against Liver Disease
- 2022
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In: New England Journal of Medicine. - 0028-4793. ; 387:4, s. 332-344
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Journal article (peer-reviewed)abstract
- BACKGROUND Exome sequencing in hundreds of thousands of persons may enable the identification of rare protein-coding genetic variants associated with protection from human diseases like liver cirrhosis, providing a strategy for the discovery of new therapeutic targets. METHODS We performed a multistage exome sequencing and genetic association analysis to identify genes in which rare protein-coding variants were associated with liver phenotypes. We conducted in vitro experiments to further characterize associations. RESULTS The multistage analysis involved 542,904 persons with available data on liver aminotransferase levels, 24,944 patients with various types of liver disease, and 490,636 controls without liver disease. We found that rare coding variants in APOB, ABCB4, SLC30A10, and TM6SF2 were associated with increased aminotransferase levels and an increased risk of liver disease. We also found that variants in CIDEB, which encodes a structural protein found in hepatic lipid droplets, had a protective effect. The burden of rare predicted loss-of-function variants plus missense variants in CIDEB (combined carrier frequency, 0.7%) was associated with decreased alanine aminotransferase levels (beta per allele, -1.24 U per liter; 95% confidence interval [CI], -1.66 to -0.83; P=4.8×10-9) and with 33% lower odds of liver disease of any cause (odds ratio per allele, 0.67; 95% CI, 0.57 to 0.79; P=9.9×10-7). Rare coding variants in CIDEB were associated with a decreased risk of liver disease across different underlying causes and different degrees of severity, including cirrhosis of any cause (odds ratio per allele, 0.50; 95% CI, 0.36 to 0.70). Among 3599 patients who had undergone bariatric surgery, rare coding variants in CIDEB were associated with a decreased nonalcoholic fatty liver disease activity score (beta per allele in score units, -0.98; 95% CI, -1.54 to -0.41 [scores range from 0 to 8, with higher scores indicating more severe disease]). In human hepatoma cell lines challenged with oleate, CIDEB small interfering RNA knockdown prevented the buildup of large lipid droplets. CONCLUSIONS Rare germline mutations in CIDEB conferred substantial protection from liver disease.
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