Eric Blanc

Berlin Institute of Health · Bioinformatics Core Unit

Background Current treatment for head and neck squamous cell carcinoma (HNSCC) involves surgery, radiotherapy, and chemotherapy. Despite aggressive multimodal approaches, tumour recurrence occurs in 40-60% of cases, leading to poor survival outcomes. HNSCC lacks common genetic drivers for tailored therapies, and reliable biomarkers for treatment se...

Background Sex differences exist in the prevalence and progression of major glomerular diseases. Podocytes are the essential cell-type in the kidney which maintain the physiological blood-urine barrier, and pathological changes in podocyte homeostasis are critical accelerators of impairment of kidney function. However, sex-specific molecular signat...

Telomere maintenance in neuroblastoma is linked to poor outcome and caused by either telomerase reverse transcriptase (TERT) activation or through alternative lengthening of telomeres (ALT). In contrast to TERT activation, commonly caused by genomic rearrangements or MYCN amplification, ALT is less well understood. Alterations at the ATRX locus are...

Single‐cell analyses can be confounded by assigning unrelated groups of cells to common developmental trajectories. For instance, cancer cells and admixed normal epithelial cells could adopt similar cell states thus complicating analyses of their developmental potential. Here, we develop and benchmark CCISM (for Cancer Cell Identification using Som...

Secondary resistance limits the clinical effectiveness of mutation-specific RAS inhibitors in colorectal cancer. It is unknown whether broad-spectrum RAS inhibitors meet similar limitations. Here, we identify and categorize mechanisms of resistance to the broad-spectrum active-state RAS inhibitor RMC-7977 in colorectal cancer cell lines. We found t...

Background Salivary gland cancers (SGC) are rare and heterogeneous malignant tumors. Advanced SGC lack established treatment options and show poor response to immunotherapy. Here, an integrative multi-omics analysis in a large cohort of advanced SGC revealed insights into the tumor immune microenvironment (TIM) and distinct mechanisms of immune eva...

Single-cell analyses can be confounded by assigning unrelated groups of cells to common developmental trajectories. For instance, cancer cells and admixed normal epithelial cells could potentially adopt similar cell states thus complicating analyses of their developmental potential. Here, we develop and benchmark CCISM (for Cancer Cell Identificati...

Neuroblastoma is a pediatric solid tumor characterized by strong clinical heterogeneity. Although clinical risk-defining genomic alterations exist in neuroblastomas, the mutational processes involved in their generation remain largely unclear. By examining the topography and mutational signatures derived from all variant classes, we identified co-o...

Background Alzheimer’s disease (AD) is characterized by the intra- and extracellular accumulation of amyloid-β (Aβ) peptides. How Aβ aggregates perturb the proteome in brains of patients and AD transgenic mouse models, remains largely unclear. State-of-the-art mass spectrometry (MS) methods can comprehensively detect proteomic alterations, providin...

Background and purpose A subgroup of salivary duct carcinoma (SDC) harbor overexpression of the androgen receptor (AR), and co-occurring mutations in the HRAS- and PIK3CA-genes. The impact of genomic complexity on targeted treatment strategies in advanced cancer is unknown. Materials and methods We analyzed molecular and clinical data from an inst...

Multiple myeloma (MM), a tumor of germinal center (GC)-experienced plasma cells, comprises distinct genetic subgroups, such as the t(11;14)/CCND1 and the t(4;14)/MMSET subtype. We have generated genetically defined, subgroup-specific MM models by the GC B cell-specific coactivation of mouse Ccnd1 or MMSET with a constitutively active Ikk2 mutant, m...

Background Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β (Aβ) peptides in intra- and extracellular deposits. How Aβ aggregates perturb the proteome in brains of patients and AD transgenic mouse models, however, remains largely unclear. State-of-the-art mass spectrometry (MS) methods can comprehensively detect proteomic...

Background The efficiency of adoptive immunotherapy correlates with the ability of the transferred T cells to release effector molecules. Furthermore, T cell memory formation is important to ensure a long lasting anti-tumor effect and thus, to prevent tumor relapse. Here, we optimized the efficacy of adoptive immunotherapy by silencing EBAG9, a neg...

Multiple myeloma is a hematologic malignancy of monoclonal plasma cells that accumulate in the bone marrow. Despite their clinical and pathophysiological relevance, the roles of bone marrow infiltrating T cells in treatment-naïve patients are incompletely understood. We investigated whether clonally expanded T cells i) were detectable in multiple m...

Telomere maintenance in neuroblastoma is linked to poor outcome and caused by either TERT activation or through alternative lengthening of telomeres (ALT). In contrast to TERT activation, commonly caused by genomic rearrangements or MYCN amplification, ALT is less well understood. Alterations at the ATRX locus are key drivers of ALT but only presen...

Chimeric antigen receptor (CAR) T cells have revolutionized treatment of B-cell malignancies. However, enhancing the efficacy of engineered T cells without compromising their safety is warranted. The estrogen receptor-binding fragment-associated antigen 9 (EBAG9) inhibits release of cytolytic enzymes from cytotoxic T lymphocytes. Here, we examined...

(1) Background: Mutation-specific T cell receptor (TCR)-based adoptive T cell therapy represents a truly tumor-specific immunotherapeutic strategy. However, isolating neoepitope-specific TCRs remains a challenge. (2) Methods: We investigated, side by side, different TCR repertoires—patients’ peripheral lymphocytes (PBLs) and tumor-infiltrating lymp...

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...

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...

Multiple myeloma (MM), a tumor of germinal center (GC)-experienced plasma cells, comprises distinct genetic subgroups, such as the t(11;14)/CCND1 and the t(4;14)/MMSET subtype. We have generated subgroup-specific MM models by the GC B cell-specific co-activation of Ccnd1 or MMSET with a constitutively active Ikk2 mutant, mimicking the secondary NFκ...

In colorectal cancer, oncogenic mutations transform a hierarchically organized and homeostatic epithelium into invasive cancer tissue lacking visible organization. We sought to define transcriptional states of colorectal cancer cells and signals controlling their development by performing single-cell transcriptome analysis of tumors and matched non...

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...

Multiple myeloma is a malignancy of monoclonal plasma cells accumulating in the bone marrow. The critical influence of tumor-infiltrating T cells on disease control and therapeutic responses has been shown in a variety of malignancies, however, the role of multiple myeloma bone marrow-infiltrating T cells is incompletely understood. Although it has...

3082 Background: KEAP1 and STK11 mutations are associated with resistance to immune checkpoint inhibition (ICI) in non-small cell lung cancer (NSCLC). Mechanisms are currently unknown. Methods: We examined mutation, methylation, copy number and gene expression data from the cancer genome atlas (TCGA) lung adenocarcinoma (LUAD), lung squamous cell c...

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Background: Reliable and reproducible interpretation of molecular aberrations constitutes a bottleneck of precision medicine. Evidence-based decision management systems may improve rational therapy recommendations. To cope with an increasing amount of complex molecular data in the clinical care of patients with cancer, we established a workflow fo...

In colorectal cancer, oncogenic mutations transform a hierarchically organized and homeostatic epithelium into invasive cancer tissue lacking visible organization. We sought to identify differences in cellular composition between normal colon and colorectal cancer, and to define signals controlling cancer cell development. We used single cell RNA a...

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,...

Background: Immune escape is one of the hallmarks of cancer and several new treatment approaches attempt to modulate and restore the immune system's capability to target cancer cells. At the heart of the immune recognition process lies antigen presentation from somatic mutations. These neo-epitopes are emerging as attractive targets for cancer imm...

Background: Mutational signatures are specific patterns of somatic mutations introduced into the genome by oncogenic processes. Several mutational signatures have been identified and quantified from multiple cancer studies, and some of them have been linked to known oncogenic processes. Identification of the processes contributing to mutations obs...

Lack of reliable peak detection impedes automated analysis of large-scale gas chromatography-mass spectrometry (GC-MS) metabolomics datasets. Performance and outcome of individual peak-picking algorithms can differ widely depending on both algorithmic approach and parameters, as well as data acquisition method. Therefore, comparing and contrasting...

Lack of reliable peak detection impedes automated analysis of large scale GC-MS metabolomics datasets. Performance and outcome of individual peak-picking algorithms can differ widely depending on both algorithmic approach and parameters as well as data acquisition method. Comparing and contrasting between algorithms is thus difficult. Here we prese...

e13033 Background: Panel sequencing (PS) has become a standard-of-care in cancer diagnostics. More comprehensive analyses such as whole-exome (WES) or RNA sequencing (RNAseq) allow for the detection of rare and unknown genetic aberrations that are not covered by predefined assays. The clinical impact of targeted versus comprehensive genomic assays...

e17577 Background: Salivary gland tumors (SGT) represent a rare and heterogeneous group of malignancies. No standard treatment exists in the advanced situation and the prognosis is poor. We here report characteristics and clinical outcomes of patients with SGT discussed at the Charité molecular tumor board (MTB). Methods: Patients with advanced can...

Dietary restriction (DR) extends animal lifespan, but imposes fitness costs. This phenomenon depends on dietary essential amino acids (EAAs) and TOR signalling, which exert systemic effects. However, the roles of specific tissues and cell-autonomous transcriptional regulators in diverse aspects of the DR phenotype are unknown. Manipulating relevant...

Self-propagating amyloid-β (Aβ) aggregates or seeds possibly drive pathogenesis of Alzheimer's disease (AD). Small molecules targeting such structures might act therapeutically in vivo. Here, a fluorescence polarization assay was established that enables the detection of compound effects on both seeded and spontaneous Aβ42 aggregation. In a focused...

Neo-epitopes are emerging as attractive targets for cancer immunotherapy and new strategies for rapid identification of relevant candidates have become a priority. We propose a method for in silico selection of candidates which have a high potential for neo-antigen generation and are likely to appear in multiple patients. This is achieved by carefu...

Dietary restriction (DR) extends animal lifespan, but imposes fitness costs. This phenomenon depends on dietary essential amino acids (EAAs) and TOR signalling, which exert systemic effects. However, the roles of specific tissues and cell-autonomous transcriptional regulators in diverse aspects of the DR phenotype are unknown. Manipulating relevant...

(Cell Metabolism 25, 610–621; March 7, 2017) In the originally published version of this article, there were errors in the amino acid ratio values reported in the Supplemental Information accompanying the manuscript. They were as follows: in Table S2, (1) the values for columns under FLYAA were a replica of MM3AA, and (2) the “ratio” columns for MM...

Movie S3. Motility and Morphology of 30 hpf sfpq−/− Embryos Rescued by Injection of Full-Length or ΔNLS Human sfpq RNA, Related to Figure 6

Movie S2. Video Showing Movement in 30 hpf sfpq−/− Embryos in Tg(Xla.Tubb2b:Hsa.MAPT-GFP)zc1 Background, Related to Figure 2

Movie S1. Video of 18–20 Somite Stage Embryos from a sfpq+/− Heterozygous Cross, Showing Spontaneous Movement in Siblings and No Movement at All in Homozygous Embryos from the Same Clutch, Related to Figure 1

Recent progress revealed the complexity of RNA processing and its association to human disorders. Here, we unveil a new facet of this complexity. Complete loss of function of the ubiquitous splicing factor SFPQ affects zebrafish motoneuron differentiation cell autonomously. In addition to its nuclear localization, the protein unexpectedly localizes...

Document S1. Supplemental Experimental Procedures, Figures S1?S7, and Tables S1 and S2

Data S1. Templates for Fly Holidic Diets and Calculator for Identifying Limiting AA See Experimental Procedures. Tab 1: Using the consumer?s average AA proportion and the AA proportions in the diet, this calculator identifies the EAA predicted to be most limiting in the diet. Text in blue is to be modified by the user; all other cells are calculat...

Balancing the quantity and quality of dietary protein relative to other nutrients is a key determinant of evolutionary fitness. A theoretical framework for defining a balanced diet would both reduce the enormous workload to optimize diets empirically and represent a breakthrough toward tailoring diets to the needs of consumers. Here, we report a si...

Genetic heterogeneity between and within tumours is a major factor determining cancer progression and therapy response. Here we examined DNA sequence and DNA copy-number heterogeneity in colorectal cancer (CRC) by targeted high-depth sequencing of 100 most frequently altered genes. In 97 samples, with primary tumours and matched metastases from 27...

List of SNVs and their allele frequency from the inter-tumor heterogeneity study. The SNVs shown here are post filtering of: non-synonymous and intronic SNVs, Sanger and SNuPE non-validated SNVs, and patient normal-tissue single nucleotide polymorphisms. A cut-off for quality of Q=50 was used. SNVs found in large repeat areas were also removed.

SNVs after filtering out non-synonymous and intronic SNVs, Sanger and SNuPE non-validated SNVs and single nucleotide polymorphisms found in the healthy normal-tissue (3.1-1). A cut-off for quality of Q=50 was used.

3D reconstruction of a stage II colon cancer rotating 360° around the horizontal axis and color coded by DNA copy number variation (CNV). Two main clusters are shown in green and violet. Red, blue and green axis key (left) indicates the x, y and z axis respectively. Z axis denominates the proximal - distal axis along the colon lumen. Distinct compa...

This application is only compatible with windows operating system. Prerequisites: Windows 7/8/10 with .net 4.5 and Direct X. First unzip the file. To install XNA run XNA Framework 4.0 Redist.msi . Next run "start3D.bat". The mesh visualization will open in a new window. Following inputs are possible while the program is running: "1", "2", "3", "4"...

Maximum likelihood parameters for a logistic model containing an interaction term, and a random effect term (the mouse) that describes the proportion of cells transduced with DUX4 or control retrovirus and expressing MyoD when exposed to Sunitinib or DMSO.(a) Maximum likelihood parameters for a logistic model containing an interaction term, and a r...

Maximum likelihood parameters for a logistic model containing an interaction term, and a random effect term (the mouse) that describes the fusion index of myoblasts transduced with DUX4 or control retrovirus and grown at high density when exposed to Sunitinib or DMSO.(a) Maximum likelihood parameters for a logistic model containing an interaction t...

Maximum likelihood parameters for a logistic model containing an interaction term, and a random effect term (the mouse) to describe MyHC expression in satellite cell-derived myoblasts expressing DUX4 or control retrovirus and exposed to Sunitinib or DMSO, when grown at low density.(a) Maximum likelihood parameters for a logistic model containing an...

A binomial model that tests the relationship between the fusion of control 54.6 and FSHD 54.12 human myoblasts relative to different doses of Sunitinib.(a) Maximum likelihood parameters for a logistic model containing an interaction term between the cell line and Sunitinib and incorporating a random effect term (the experiment). The model is a bino...

A binomial model evaluating whether the proportion of LAMIN A/C+ nuclei derived from grafted FSHD 54.12 human myoblasts in a muscle fibre is significantly affected by exposure to Sunitinib.(a) Maximum likelihood parameters for a logistic model containing a random effect term (the mouse) describing the probability of a human LAMIN A/C+ nuclei being...

A binomial model evaluating whether the proportion of muscle fibres containing SPECTRIN and LAMIN A/C derived from grafted FSHD 54.12 human myoblasts is significantly affected by exposure to Sunitinib.(a) Maximum likelihood parameters for a logistic model containing a random effect term (the mouse) describing the probability of a SPECTRIN+ murine m...

Maximum likelihood parameters for a logistic model containing an interaction term and a random effect (mouse) to describe the effect of CA RET51 (RET51-MENA) expression and Sunitinib, TG101209 or Zactima on fusion in C2C12 myoblasts.(a) Maximum likelihood parameters for a logistic model containing an interaction term and a random effect (mouse) to...

Maximum likelihood parameters for a logistic model containing an interaction term, and a random effect term (the mouse) that describes the proportion of myoblasts transduced with DUX4 or control retrovirus and incorporating EdU when exposed to Sunitinib or DMSO.(a) Maximum likelihood parameters for a logistic model containing an interaction term, a...

Maximum likelihood parameters for a logistic model containing an interaction term, and a random effect term describing the probability of a nucleus being present in a MyHC+ cell.(a) Maximum likelihood parameters for a logistic model containing an interaction term, and a random effect term (the mouse) describing the probability of a nucleus being pr...

Quasi-Poisson model parameters for a fixed-effects factorial model incorporating a parameter to account for the replicate effects (Batch) on the number of cells expressing CA RET51 (RET51-MEN2A) or control when treated with different concentrations of Sunitinib, TG101209 or Zactima.The significance of each effect and combined effects relative to th...

Maximum likelihood parameters for a logistic model containing an interaction term, and a random effect term (the mouse) to describe MyoG expression in satellite cell-derived myoblasts expressing DUX4 or control retrovirus and exposed to Sunitinib or DMSO, when grown at low density.(a) Maximum likelihood parameters for a logistic model containing an...

A binomial model that tests the relationship between the proliferation of control 54.6 and FSHD 54.12 human myoblasts with different doses of Sunitinib.(a) Maximum likelihood parameters for a logistic model containing an interaction term between the cell line and sunitinib and incorporating a random effect term (the experiment). The model is a bino...

Maximum likelihood parameters for a logistic model containing an interaction term between DUX4 and Sunitinib that describes the fusion index of satellite-cells grown at high density with or without DUX4 transduction.(a) Maximum likelihood parameters for a logistic model containing an interaction term between DUX4 expression and Sunitinib during fus...

A linear model that describes the relationship between the shape (eccentricity) of control 54.6 and FSHD 54.12 human myoblasts relative to different doses of Sunitinib.The model is a linear model that describes the relationship between the shape (eccentricity) of 54.6 (control) and 54.12 (FSHD) cells relative to different doses of Sunitinib. P valu...

Facioscapulohumeral muscular dystrophy (FSHD) involves sporadic expression of DUX4, which inhibits myogenesis and is pro-apoptotic. To identify target genes, we over-expressed DUX4 in myoblasts and found that the receptor tyrosine kinase Ret was significantly up-regulated, suggesting a role in FSHD. RET is dynamically expressed during myogenic prog...

Animal lifespan can be extended by dietary restriction (DR), but at a cost to fitness. This phenomenon depends on essential amino acids (EAAs) and TOR signalling, but roles of specific tissues and downstream transcriptional regulators are poorly characterised. Manipulating relevant transcription factors (TFs) specifically in lifespan-limiting tissu...

Appendix

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