Joern Toedling's research while affiliated with NUVISAN Pharma Services and other places

Publications (91)

Article
Full-text available
Recent evidence demonstrates that colon cancer stem cells (CSCs) can generate neurons that synapse with tumor innervating fibers required for tumorigenesis and disease progression. Greater understanding of the mechanisms that regulate CSC driven tumor neurogenesis may therefore lead to more effective treatments. RNA-sequencing analyses of ALDHPosit...
Preprint
Neuroblastoma is a pediatric solid tumor characterized by strong clinical heterogeneity. Although certain complex genomic alterations, such as extrachromosomal DNA amplifications (ecDNA), have been recurrently detected in neuroblastomas, the mutational processes involved in their generation remain largely unclear. By examining the topography of com...
Article
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Intratumour heterogeneity is a major cause of treatment failure in cancer. We present in-depth analyses combining transcriptomic and genomic profiling with ultra-deep targeted sequencing of multiregional biopsies in 10 patients with neuroblastoma, a devastating childhood tumour. We observe high spatial and temporal heterogeneity in somatic mutation...
Article
Full-text available
Very high risk neuroblastoma is characterised by increased MAPK signalling, and targeting MAPK signalling is a promising therapeutic strategy. We used a deeply characterised panel of neuroblastoma cell lines and found that the sensitivity to MEK inhibitors varied drastically between these cell lines. By generating quantitative perturbation data and...
Preprint
Full-text available
Very high risk neuroblastoma is characterised by increased MAPK signalling, and targeting MAPK signalling is a promising therapeutic strategy. We used a deeply characterised panel of neuroblastoma cell lines and found that the sensitivity to MEK inhibitors varied drastically between these cell lines. By generating quantitative perturbation data and...
Article
Full-text available
Recent data suggests that therapy resistant quiescent cancer stem cells (qCSCs) are the source of relapse in colon cancer. Here, using colon cancer patient-derived organoids (PDOs) and xenografts (PDXs), we identify rare long-term label-retaining qCSCs that can re-enter the cell cycle to generate new tumors. RNA-sequencing analyses demonstrated tha...
Preprint
Full-text available
Recent data suggests that colon tumors contain a subpopulation of therapy resistant quiescent cancer stem cells (qCSCs) that are the source of relapse following treatment. Here, using colon cancer patient-derived organoids (PDOs) and xenograft (PDX) models, we identify a rare population of long-term label-retaining (PKH26Positive) qCSCs that can re...
Preprint
Full-text available
Recent data support a hierarchical model of colon cancer driven by a population of cancer stem cells (CSCs). Greater understanding of the mechanisms that modulate CSCs may therefore lead to more effective treatments. Serial limiting dilution xenotransplantation assays of colon cancer patient-derived tumors demonstrated ALDH-Positive cells to be enr...
Article
Full-text available
MYCN amplification drives one in six cases of neuroblastoma. The supernumerary gene copies are commonly found on highly rearranged, extrachromosomal circular DNA (ecDNA). The exact amplicon structure has not been described thus far and the functional relevance of its rearrangements is unknown. Here, we analyze the MYCN amplicon structure using shor...
Article
Full-text available
Detection and characterization of cell-free DNA (cfDNA) in peripheral blood from neuroblastoma patients may serve as a minimally invasive liquid biopsy approach. Major challenges of cfDNA analysis purified from blood samples are small sample volumes and low cfDNA concentrations. Droplet digital PCR (ddPCR) is a suitable technology to analyze low le...
Article
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An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Article
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Extrachromosomal circularization of DNA is an important genomic feature in cancer. However, the structure, composition and genome-wide frequency of extrachromosomal circular DNA have not yet been profiled extensively. Here, we combine genomic and transcriptomic approaches to describe the landscape of extrachromosomal circular DNA in neuroblastoma,...
Preprint
Full-text available
MYCN amplification drives one in six cases of neuroblastoma. The supernumerary gene copies are commonly found on highly rearranged, extrachromosomal circular DNA. The exact amplicon structure has not been described thus far and the functional relevance of its rearrangements is unknown. Here, we analyzed the MYCN amplicon structure and its chromatin...
Article
Full-text available
Accurate modeling of intratumor heterogeneity presents a bottleneck against drug testing. Flexibility in a preclinical platform is also desirable to support assessment of different endpoints. We established the model system, OHC‐NB1, from a bone marrow metastasis from a patient diagnosed with MYCN‐amplified neuroblastoma and performed whole‐exome s...
Conference Paper
p>Circular RNAs (circRNAs), a noncoding RNA class originating from alternative splicing, are highly abundant in neural tissues and can regulate gene expression by binding to and inhibiting microRNAs and RNA-binding proteins. We explored whether circRNAs influence pathogenesis in neuroblastoma, the most common solid extracranial tumor of childhood....
Article
The lactate transporter SLC16A1/MCT1 plays a central role in tumor cell energy homeostasis. In a cell based screen, we identified a novel class of monocarboxylate transporter 1 (MCT1) inhibitors, including BAY-8002, which potently suppress bidirectional lactate transport. We investigated the antiproliferative activity of BAY-8002 in a panel of 246...
Article
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Metabolic changes are linked to epigenetic reprogramming and play important roles in several tumor types. PGC-1α is a transcriptional coactivator controlling mitochondrial biogenesis and is linked to oxidative phosphorylation. We provide evidence that melanoma models with elevated PGC-1α levels are characteristic of the proliferative phenotype and...
Article
Full-text available
Fewer than 50% of patients with high-risk neuroblastoma survive five years after diagnosis with current treatment protocols. Molecular targeted therapies are expected to improve survival. Although MDM2 has been validated as a promising target in preclinical models, no MDM2 inhibitors have yet entered clinical trials for neuroblastoma patients. Toxi...
Poster
Recent data support a hierarchical model of colon cancer in which tumor growth is driven by a subpopulation of cancer stem cells (CSCs) that may also be the source of relapse following treatment. Elucidation of the cellular heterogeneity within a tumor would therefore facilitate better characterization of patient subtypes and lead to more personali...
Conference Paper
Growing evidence supports a subpopulation of cancer stem cells (CSCs) as both the drivers of tumor growth and the source of relapse following treatment. The identification of genes and pathways required for the survival of CSCs may therefore lead to better treatment outcomes. Here, as part of the OncoTrack* consortium, we report the use of 3D in vi...
Poster
Recent data support a hierarchical model of colon cancer in which tumor growth is driven by a subpopulation of cancer stem cells (CSCs) that may also be the source of relapse following treatment. Elucidation of the cellular heterogeneity within a tumor would therefore facilitate better characterization of patient subtypes and lead to more personali...
Article
Full-text available
The epithelial to mesenchymal transition (EMT) is a biological process in which cells lose cell-cell contacts and become motile. EMT is used during development, for example, in triggering neural crest migration, and in cancer metastasis. Despite progress, the dynamics of JNK signaling, its role in genomewide transcriptional reprogramming, and invol...
Article
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Exosomes are small membranous vesicles of endocytic origin that are released by almost every cell type. They exert versatile functions in intercellular communication important for many physiological and pathological processes. Recently, exosomes attracted interest with regard to their role in cell–cell communication in the nervous system. We have s...
Article
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Unlabelled: The intestinal tract is the largest reservoir of microbes in the human body. The intestinal microbiota is thought to be able to modulate alterations of the gut induced by enteropathogens, thereby maintaining homeostasis. Listeria monocytogenes is the agent of listeriosis, an infection transmitted to humans upon ingestion of contaminate...
Article
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Non-coding RNA (ncRNA) PROfiling in small RNA (sRNA)-seq (ncPRO-seq) is a stand-alone, comprehensive and flexible ncRNA analysis pipeline. It can interrogate and perform detailed profiling analysis on sRNAs derived from annotated non-coding regions in miRBase, Rfam and RepeatMasker, as well as specific regions defined by users. The ncPRO-seq pipeli...
Data
Expression of various markers during ES cell differentiation. Time-course quantification of the indicated markers was carried out in 4 distinct ES cell lines in two independent differentiation events. The values obtained for the two independent female cell lines (PGK, XX1; LF2, XX2) and male cell lines (E14, XY1; HM1, XY2) were averaged and are pre...
Data
Differentially expressed microRNAs between ES male and female cells. miRNA read counts per library were normalised and tested for differential analysis using the DESeq package [14]. (XLS)
Data
Fold-changes of microRNA reads counts between female and male ES cells across sequencing platform. For all microRNAs and miR* investigated, we computed the fold-changes between female and male cells within one sequencing platform first (for Solexa: ES_XX_Solexa_i_IDT/ES_XY_Solexa_i_IDT; for SOLiD: ES_XX_SOLID_v4/ES_XY_SOLID_v4). The logarithms of t...
Data
Significance of PAM classes as assessed by bootstrapping. The histogram represents the number of pairs from the same miRNA cluster in the same PAM classes (k = 3) for 1,000 random permutations of all miRNA expression data (bootstrapping). The red point represents the number of miRNAs in the same PAM class as found in the real dataset. The four exam...
Data
Size distribution and annotation of cloned small RNAs. (A) Size distribution of small RNAs cloned from male (XY1, E14) and female (XX1, PGK) mouse undifferentiated ES cells (D0), after two or five days of differentiation (D2 and D5). The data indicate a population with a median at 22–23 nucleotides. (B) The origin of cloned small RNAs is indicated...
Data
Gaussian mixture model of MicroRNA distribution. The distribution of miRNA frequency was fitted with a Gaussian mixture model. A Bayesian information criterion (BIC) allowed selection of two components. The first component is truncated at zero and corresponds to miRNAs with low counts (interpreted as background). The second component corresponds to...
Data
microRNA reads counts. Aligned reads of length 19–26 nt were considered to correspond to a mature miRNA (or miR*) only if the aligned position did not differ from the annotated position of the mature miRNA (or miR*) by more than 2 bp and if the reads had at most as many genomic match positions as the number of genomic copies of the respective matur...
Data
Comparison of miRNA expression levels between libraries from the two cell lines and the same sequencing technology. Scatter plots comparing the normalised miRNA expression levels (on a generalised logarithmic scale) between E14 XY (y-axis) and PGK XX (x-axis) libraries generated using the same sequencing technology and library preparation protocols...
Article
Full-text available
Second-generation sequencing is a powerful method for identifying and quantifying small-RNA components of cells. However, little attention has been paid to the effects of the choice of sequencing platform and library preparation protocol on the results obtained. We present a thorough comparison of small-RNA sequencing libraries generated from the s...
Data
Comparison of miRNA expression levels between libraries from the same cell line and different sequencing technology. Scatter plots comparing the normalised miRNA expression levels (on a generalised logarithmic scale) between pairs of libraries generated from the E14 cell line but using different sequencing technologies. Libraries are named as in Ta...
Data
miR/miR* ratios. Number of miR/miR* pairs with more reads for the passenger star form than for the mature miRNA per library. (XLS)
Article
Full-text available
Mammalian cells possess two isoforms of the histone H3-H4 chaperone anti-silencing function 1 (Asf1), Asf1a and Asf1b. However to date, whether they have individual physiological roles has remained elusive. Here, we aim to elucidate the functional importance of Asf1 isoforms concerning both basic and applied aspects. First, we reveal a specific pro...
Article
Full-text available
The R/Bioconductor package girafe facilitates the functional exploration of alignments of sequence reads from next-generation sequencing data to a genome. It allows users to investigate the genomic intervals together with the aligned reads and to work with, visualise and export these intervals. Moreover, the package operates within and extends the...
Data
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A figure showing Hoechst nuclear staining of dividing cdc28-ts mutant cells. Control data displaying synchronous division of the yeast cells along with the cell cycle progression. Each image represents a gallery of approximately 10 to 20 representative cells that were chosen, for the respective time-point, from different fields of view. Criteria of...
Data
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A figure showing a comparison of the relative timing of expression within 13 periodic SAPs. We calculated the peak-time difference for the periodic sense and antisense transcripts within each of the 13 cycling SAPs for the alpha-factor and Cdc28 experiments separately. A difference of 0 corresponds to in-phase expression, whereas a difference of 50...
Data
A figure showing GO categories of 109 periodic ORFs unique to our dataset. The x-axis displays the number of genes and the y-axis shows the names of GO categories.
Data
A table listing antisense and novel intergenic transcripts identified in our study. Excel sheet 1 is a table of all 523 antisense transcripts, characterized by their genomic position, length and overlapping sense feature; sheet 2 is a table of all 135 unannotated intergenic transcripts, categorized by genomic position and length. Cycling intergenic...
Data
A table listing periodic protein-coding genes, antisense and unannotated intergenic transcripts. Excel sheet 1 lists 598 periodic ORFs identified in our dataset, sheet 2 lists 37 cycling antisense transcripts, and sheet 3 lists 11 periodic unannotated intergenic transcripts.
Data
A table listing the 109 periodic ORFs identified in our study.
Data
Full-text available
A figure showing GO categories of 443 non-periodic ORFs opposite non-periodic antisense transcripts. The x-axis displays the number of genes and the y-axis shows the names of GO categories.
Data
A contingency table for sense-antisense transcript overlap.
Data
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A figure showing categories of expressed segments. The pie chart shows the categories and the numbers of all identified transcribed segments. The unassigned categories encompass the segments that did not meet filter criteria and were excluded from further analyses [11]; correspondingly, the filtered categories are those that did pass the filtering...
Data
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A figure showing a comparison of our dataset with the published datasets on the cell cycle in yeast. Three ROC-like plots compare: (a) our combined dataset with that of Gauthier et al. [37]; (b) our cdc28 dataset with the other Cdc28 datasets of Spellman et al. [30] and Cho et al. [28]; (c) our alpha-factor dataset with the existing alpha-factor da...
Article
Full-text available
Extensive transcription of non-coding RNAs has been detected in eukaryotic genomes and is thought to constitute an additional layer in the regulation of gene expression. Despite this role, their transcription through the cell cycle has not been studied; genome-wide approaches have only focused on protein-coding genes. To explore the complex transcr...
Data
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A figure showing heatmaps of bi-directional expression of neighboring cell cycle-regulated genes that share transcription regulatory elements. (a) Two neighboring ORFs: TEL2 and ESP1. (b) ORF and an antisense transcript of the upstream protein-coding gene: SPT21 and antisense counterpart of YMR178W. (c) ORF and cycling unannotated intergenic transc...
Data
A Word document providing supplemental data. The file provides additional information on the following sections: 1, Determination of the boundaries of the cell cycle phases; 2, Conservation analysis of non-coding RNAs; 3, Analysis of upstream regulatory elements for periodic unannotated transcripts; 4, UTR lengths; 5, Divergently transcribed period...