A5056033164- Protein Degradation and Inhibitors
- Sarcoma Diagnosis and Treatment
- Telomeres, Telomerase, and Senescence
- MicroRNA in disease regulation
- CRISPR and Genetic Engineering
- Epigenetics and DNA Methylation
- Cancer-related Molecular Pathways
- Cancer Genomics and Diagnostics
- Chromatin Remodeling and Cancer
- Advanced biosensing and bioanalysis techniques
- Histone Deacetylase Inhibitors Research
- Cancer-related gene regulation
- Pluripotent Stem Cells Research
- Immune Cell Function and Interaction
- Immune cells in cancer
- RNA modifications and cancer
- CAR-T cell therapy research
- Renal and related cancers
- Genomics and Chromatin Dynamics
- Ubiquitin and proteasome pathways
- Neuroblastoma Research and Treatments
- Tumors and Oncological Cases
- Tissue Engineering and Regenerative Medicine
- Genetic factors in colorectal cancer
- Cancer-related molecular mechanisms research
Heidelberg University
2019-2025
Hopp Children's Cancer Center Heidelberg
2019-2025
German Cancer Research Center
2019-2025
National Center for Tumor Diseases
2024-2025
University Hospital Heidelberg
2025
Deutschen Konsortium für Translationale Krebsforschung
2021-2025
Hammersmith Hospital
2009-2024
Imperial College London
2008-2024
Memorial Sloan Kettering Cancer Center
2013-2023
Spanish National Cancer Research Centre
2022
Somatic cells can be reprogrammed into induced pluripotent stem (iPS) by overexpressing combinations of factors such as Oct4, Sox2, Klf4, and c-Myc. Reprogramming is slow stochastic, suggesting the existence barriers limiting its efficiency. Here we identify senescence one barrier. Expression four reprogramming triggers up-regulating p53, p16 INK4a , p21 CIP1 . Induction DNA damage response chromatin remodeling INK4a/ARF locus are two mechanisms behind induction. Crucially, ablation...
The INK4a/ARF tumor suppressor locus, a key executor of cellular senescence, is regulated by members the Polycomb group (PcG) transcriptional repressors. Here we show that signaling from oncogenic RAS overrides PcG-mediated repression INK4a activating H3K27 demethylase JMJD3 and down-regulating methyltransferase EZH2. In human fibroblasts, activates , but not ARF causes p16 -dependent arrest. mouse embryo Jmjd3 both Ink4a Arf elicits p53-dependent arrest, echoing effects in this system. Our...
Oncogene-induced senescence is a potent barrier to tumorigenesis that limits cellular expansion following certain oncogenic events. Senescent cells display repressive chromatin configuration thought stably silence proliferation-promoting genes while simultaneously activating an unusual form of immune surveillance involving secretory program referred as the senescence-associated phenotype (SASP). Here, we demonstrate also involves global remodeling enhancer landscape with recruitment reader...
The Polycomb Group (PcG) of chromatin modifiers regulates pluripotency and differentiation. Mammalian genomes encode multiple homologs the repressive complex 1 (PRC1) components, including five orthologs Drosophila protein (Cbx2, Cbx4, Cbx6, Cbx7, Cbx8). We have identified Cbx7 as primary ortholog PRC1 complexes in embryonic stem cells (ESCs). expression is downregulated during ESC differentiation, preceding upregulation Cbx2, Cbx8, which are directly repressed by Cbx7. Ectopic inhibits...
Abstract Mutations in the TP53 tumor suppressor gene are common many cancer types, including acute myeloid leukemia (AML) subtype known as complex karyotype AML (CK-AML). Here, we identify a gain-of-function (GOF) Trp53 mutation that accelerates CK-AML initiation beyond p53 loss and, surprisingly, is required for disease maintenance. The Trp53R172H (TP53R175H humans) exhibits neomorphic function by promoting aberrant self-renewal leukemic cells, phenotype present hematopoietic stem and...
Abstract Linking clinical multi-omics with mechanistic studies may improve the understanding of rare cancers. We leverage two precision oncology programs to investigate rhabdomyosarcoma FUS/EWSR1-TFCP2 fusions, an orphan malignancy without effective therapies. All tumors exhibit outlier ALK expression, partly accompanied by intragenic deletions and aberrant splicing resulting in variants that are oncogenic sensitive inhibitors. Additionally, recurrent CKDN2A/MTAP co-deletions provide a...
Poorly differentiated thyroid carcinomas (PDTC) represent a heterogeneous, aggressive entity, presenting features that suggest progression from well-differentiated carcinomas. To elucidate the mechanisms underlying such and identify novel therapeutic targets, we assessed genome-wide expression in normal tumour tissues.Microarray analyses of 24 - 7 classic papillary, 8 follicular variants papillary (fvPTC), 4 (FTC) 5 PDTC were performed correlated with RAS, BRAF, RET/PTC PAX8-PPARG...
Expression of the transcription factors OCT4, SOX2, KLF4, and cMYC (OSKM) reprograms somatic cells into induced pluripotent stem (iPSCs). Reprogramming is a slow inefficient process, suggesting presence safeguarding mechanisms that counteract cell fate conversion. One such mechanism senescence. To identify modulators reprogramming-induced senescence, we performed genome-wide shRNA screen in primary human fibroblasts expressing OSKM. In screen, identified novel mediators OSKM-induced...
Oncogene-induced senescence (OIS) is a potent tumor suppressor mechanism. To identify regulators relevant to cancer, we screened an shRNA library targeting genes deleted in hepatocellular carcinoma (HCC). Here, describe how knockdown of the SWI/SNF component ARID1B prevents OIS and cooperates with RAS induce liver tumors. controls p16INK4a p21CIP1a transcription but also regulates DNA damage, oxidative stress, p53 induction, suggesting that uses additional mechanisms regulate senescence....
Reduced protein levels of SMARCB1 (also known as BAF47, INI1, SNF5) have long been observed in synovial sarcoma. Here, we show that combined Smarcb1 genetic loss with SS18-SSX expression mice synergized to produce aggressive tumors histomorphology, transcriptomes, and genome-wide BAF-family complex distributions distinct from alone, indicating a defining role for silencing alone mesenchyme modeled epithelioid sarcomagenesis. In mouse human sarcoma cells, was identified within PBAF canonical...
Large-scale genome sequencing efforts of human tumours identified epigenetic modifiers as one the most frequently mutated gene class in cancer. However, how these mutations drive tumour development and progression are largely unknown. Here, we investigated function histone demethylase KDM6A gastrointestinal cancers, such liver cancer pancreatic cancer.Genetic alterations well expression analyses were performed patients with Genetic mouse models coupled Kdm6a-deficiency investigated,...
The survival rate among children with relapsed tumors remains poor, due to tumor heterogeneity, lack of directly actionable drivers and multidrug resistance. Novel personalized medicine approaches tailored each are urgently needed improve cancer treatment. Current pediatric precision oncology platforms, such as the INFORM (INdividualized Therapy FOr Relapsed Malignancies in Childhood) study, reveal that molecular profiling tissue identifies targets associated clinical benefit a subgroup...
Linkage analysis has identified four familial non-medullary thyroid carcinoma (FNMTC) susceptibility loci: fPTC/PRN (1p13.2-1q22), NMTC1 (2q21), MNG1 (14q32) and TCO (19p13.2). To date, there is no evidence for the involvement of genes from RAS/RAF signalling pathway in FNMTC. The aim our study was to evaluate role loci, genes, In total, 8 FNMTC families, 27 lesions family members (22 papillary carcinomas (PTCs): 11 classic, 10 follicular variant 1 mixed variant; 4 adenomas (FTAs) nodular...