A5049556449- Cancer-related Molecular Pathways
- Cancer, Hypoxia, and Metabolism
- Cancer Genomics and Diagnostics
- Cancer Research and Treatments
- Melanoma and MAPK Pathways
- Cutaneous Melanoma Detection and Management
- Computational Drug Discovery Methods
- Genomic variations and chromosomal abnormalities
- Single-cell and spatial transcriptomics
- Microtubule and mitosis dynamics
- Genomics and Chromatin Dynamics
- Cell Image Analysis Techniques
- Cancer Cells and Metastasis
- Pancreatic and Hepatic Oncology Research
- Sarcoma Diagnosis and Treatment
- vaccines and immunoinformatics approaches
- Lung Cancer Treatments and Mutations
- Lung Cancer Research Studies
- DNA Repair Mechanisms
- Genetics and Neurodevelopmental Disorders
- MicroRNA in disease regulation
- Ubiquitin and proteasome pathways
- Forest Management and Policy
- Caveolin-1 and cellular processes
- RNA Research and Splicing
University of Groningen
2015-2024
University Medical Center Groningen
2015-2024
Abstract The phenomenon of mixed/heterogenous treatment responses to cancer therapies within an individual patient presents a challenging clinical scenario. Furthermore, the molecular basis mixed intra-patient tumor remains unclear. Here, we show that patients with metastatic lung adenocarcinoma harbouring co-mutations EGFR and TP53 , are more likely have tyrosine kinase inhibition (TKI), compared those mutation alone. combined presence whole genome doubling (WGD) leads increased instability...
Alzheimer's disease (AD) is a neurodegenerative of the brain and most common form dementia in elderly. Aneuploidy, state which cells have an abnormal number chromosomes, has been proposed to play role neurodegeneration AD patients. Several studies using fluorescence situ hybridization shown that brains patients contain increased aneuploid cells. However, because reported rate aneuploidy neurons ranges widely, more sensitive method needed establish possible pathology. In current study, we...
Abstract Understanding the evolutionary pathways to metastasis and resistance immune-checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here, we present most comprehensive intrapatient metastatic dataset assembled date as part of Posthumous Evaluation Advanced Cancer Environment (PEACE) research autopsy program, including 222 exome sequencing, 493 panel-sequenced, 161 RNA 22 single-cell whole-genome sequencing samples from 14 ICI-treated patients. We observed...
Therapeutic resistance and recurrence remain core challenges in cancer therapy. How therapy arises is currently not fully understood with tumors surviving via multiple alternative routes. Here, we demonstrate that a subset of cells survives therapeutic stress by entering transient state characterized whole-genome doubling. At the onset polyploidization program, identified an upregulation key transcriptional regulators, including early stress-response protein AP-1 normoxic stabilization...
Immune cell-type specific miRNA expression patterns have been described but the detailed role of single miRNAs in function T-cells remains largely unknown. We investigated miR-21 primary human CD4+ T-cells. MiR-21 is substantially expressed with a memory phenotype, and robustly upregulated upon αCD3/CD28 activation both naive By inhibiting endogenous activated T-cells, we showed that regulates fundamentally different aspects T-cell biology, depending on differentiation status T-cell. Stable...
Circulating tumor cells (CTCs) detected by CellSearch are prognostic in non-small-cell lung cancer (NSCLC), but rarely found. CTCs can be extracted from the blood together with mononuclear cell populations diagnostic leukapheresis (DLA), therefore concentrating them. However, only process limited DLA volumes (≈2 mL). Therefore, we established a protocol to enumerate products Isolation SizE of Tumor (ISET), and compared CTC counts between CellSearch® ISET. was performed NSCLC patients who...
Abstract TP53 is the most frequently mutated gene in human cancer. This shows not only loss‐of‐function mutations but also recurrent missense with gain‐of‐function activity. We have studied primary bone malignancy osteosarcoma, which harbours one of rearranged genomes all cancers. odd since it primarily affects children and adolescents who lived long life thought necessary to accumulate massive numbers mutations. In often disrupted by structural variants. Here, we show through combined...
Abstract Purpose: Tumor cells from patients with lung cancer are expelled the primary tumor into blood, but difficult to detect in peripheral circulation. We studied release of circulating (CTCs) during surgery test hypothesis that CTC counts influenced by hemodynamic changes (caused surgical approach) and manipulation. Experimental Design: Patients undergoing video-assisted thoracic (VATS) or open for (suspected) were included. Blood samples taken before (T0) radial artery (RA), both RA...
Abstract Polyploidization frequently precedes tumorigenesis but also occurs during normal development in several tissues. Hepatocyte ploidy is controlled by the PIDDosome and regeneration. This multi‐protein complex activated supernumerary centrosomes to induce p53 restrict proliferation of polyploid cells, otherwise prone for chromosomal instability. deficiency liver results drastically increased polyploidy. To investigate PIDDosome‐induced p53‐activation pathogenesis cancer, we chemically...
While comprehensive molecular profiling of histone H3.3 mutant pediatric high-grade glioma has revealed extensive dysregulation the chromatin landscape, exact mechanisms driving tumor formation remain poorly understood. Since gliomas also exhibit high levels copy number alterations, we set out to address if H3.3K27M oncohistone leads destabilization genome. Hereto, established a cell culture model allowing inducible expression and observed an increase in mitotic abnormalities. We found...
Chemotherapy resistance and relapses are common in high-risk neuroblastoma (NB). Here, we developed a clinically relevant vivo treatment protocol mimicking the first-line five-chemotherapy regimen of NB applied this to mice with MYCN -amplified patient-derived xenografts (PDXs). Genomic transcriptomic analyses were used reveal chemoresistance mechanisms. Intrinsic was associated high genetic diversity an embryonic phenotype. Relapsed acquired showed decreased adrenergic phenotype enhanced...
Abstract High hyperdiploid acute lymphoblastic leukemia (HeH ALL), one of the most common childhood malignancies, is driven by nonrandom aneuploidy (abnormal chromosome numbers) mainly comprising chromosomal gains. In this study, we investigate how in HeH ALL arises. Single cell whole genome sequencing 2847 cells from nine primary cases and normal bone marrow reveals that generally display low heterogeneity, indicating they are not characterized instability showing aneuploidy-driven...
Chromosomal instability (CIN) and aneuploidy are hallmarks of cancer. As most cancers aneuploid, targeting or CIN may be an effective way to target a broad spectrum cancers. Here, we perform two small molecule compound screens identify drugs that selectively cells aneuploid exhibit phenotype. We find much more sensitive the energy metabolism regulating drug ZLN005 than their euploid counterparts. Furthermore, with ongoing phenotype, induced by spindle assembly checkpoint (SAC) alleviation,...
Abstract Osteoblastoma is a locally aggressive tumour of bone. Until recently, its underlying genetic features were largely unknown. During the past two years, reports have demonstrated that acquired structural variations affect transcription factor FOS in high proportion cases. These rearrangements modify terminal exon gene and are believed to stabilise both transcript encoded protein, resulting expression levels. Here, we applied in‐depth analyses series 29 osteoblastomas, including five...
Abstract Amplification of the MDM2 and CDK4 genes on chromosome 12 is commonly associated with low-grade osteosarcomas. In this study, we conducted high-resolution genomic transcriptomic analyses 33 samples from 25 osteosarcomas, encompassing both high- cases and/or amplification. We discerned four major subgroups, ranging nearly intact genomes to heavily rearranged ones, each harbouring amplification or TP53 structural alterations. While amplicons involving exhibited signs an initial...
CONTEXT Cardiopulmonary bypass (CPB) is a commonly used technique in cardiac surgery but associated with acute, transient, renal dysfunction that has negative impact on long-term survival. OBJECTIVE To unravel the molecular pathogenesis of injury following CPB. DESIGN obtain insight into CPB, we performed microarray analysis gene expression rat. SETTING University Medical Centre Groningen. INTERVENTION Rats underwent CPB or sham procedure for 60 min and were sacrificed at min, 1 5 days after...
<p>Figure S2: Brightfield images of cell lines after treatment with LD50 cisplatin.</p>