A5018784926- Cancer-related Molecular Pathways
- RNA modifications and cancer
- Ocular Oncology and Treatments
- Epigenetics and DNA Methylation
- Ubiquitin and proteasome pathways
- Sarcoma Diagnosis and Treatment
- Immunotherapy and Immune Responses
- Retinal Development and Disorders
- Virus-based gene therapy research
- Cancer Cells and Metastasis
- Cancer Genomics and Diagnostics
- Hedgehog Signaling Pathway Studies
- interferon and immune responses
- Hippo pathway signaling and YAP/TAZ
- 14-3-3 protein interactions
- CAR-T cell therapy research
- Cell death mechanisms and regulation
- Melanoma and MAPK Pathways
- Cancer, Lipids, and Metabolism
- Histone Deacetylase Inhibitors Research
- CRISPR and Genetic Engineering
- DNA Repair Mechanisms
- RNA Research and Splicing
- Immune cells in cancer
- Protein Degradation and Inhibitors
Leiden University Medical Center
2014-2024
Leiden University
1997-2022
Oncode Institute
2020-2021
University Medical Center Utrecht
2015-2017
Cancer Genomics Centre
2014
Martin Luther University Halle-Wittenberg
2012
Ludwig Cancer Research
2012
University of Oxford
2012
Wittenberg University
2012
Tel Aviv University
2005
Maintenance of genomic stability depends on the DNA damage response, an extensive signaling network that is activated by lesions such as double-strand breaks (DSBs). The primary activator mammalian DSB response nuclear protein kinase ataxia–telangiectasia, mutated (ATM), which phosphorylates key players in various arms this network. activation and stabilization p53 play a major role are mediated ATM-dependent posttranslational modifications Mdm2, ubiquitin ligase p53. p53's to also...
AbstractUnderstanding how p53 activity is regulated crucial in elucidating mechanisms of cellular defense against cancer. Genetic data indicate that Mdmx as well Mdm2 plays a major role maintaining at low levels nonstressed cells. However, biochemical regulates are not understood. Through identification Mdmx-binding proteins, we found 14-3-3 proteins associated with Mdmx. harbors consensus sequence for binding 14-3-3. Serine 367 (S367) located within the putative 14-3-3, and its substitution...
Purpose.: Uveal melanoma (UM) is fatal in up to 50% of patients because liver metastases that are refractory therapies currently available. While murine xenograft models for human uveal available, they have limited utility screening large compound libraries drug discovery studies. Therefore, new robust preclinical needed can efficiently evaluate efficacy treatment this malignancy. Methods.: cell lines generated from primary tumors (92.1, Mel270) and (OMM2.3, OMM2.5, OMM1) were injected into...
The p53 tumor suppressor plays a major role in maintaining genomic stability. Its activation and stabilization response to double strand breaks (DSBs) DNA are regulated primarily by the ATM protein kinase. mediates several posttranslational modifications on itself, as well phosphorylation of p53's essential inhibitors, Hdm2 Hdmx. Recently we showed that ATM- Hdm2-dependent ubiquitination subsequent degradation Hdmx following DSB induction mediated S403, S367, S342, with S403 being targeted...
Conventional high-grade osteosarcoma is the most common primary bone malignancy. Although altered expression of p53 inhibitor HDMX (Mdmx/Mdm4) associated with cancer risk, progression, and outcome in other tumor types, little known about its role osteosarcoma. High Hdmx splice variant HDMX-S relative to full-length transcript (the HDMX-S/HDMX-FL ratio) correlates reduced protein expression, faster poorer survival several cancers. Here, we show that ratio positively less metastatic a trend...
Abstract Translocations involving ETS ‐transcription factors, most commonly leading to the EWSR1–FLI1 fusion protein, are hallmark of Ewing sarcoma. Despite knowledge this driving molecular event, an effective therapeutic strategy is lacking. To test potential treatment regimes, we established a novel sarcoma zebrafish engraftment model allowing time‐effective, dynamic quantification progression and tumour burden in vivo , applicable for screening single combined compounds. In...
Abstract The function of the tumor suppressor p53 is universally compromised in cancers. It most frequently mutated gene human cancers (reviewed). In cases where not mutated, alternative regulatory pathways inactivate its suppressive functions. This primarily achieved through elevation expression key inhibitors p53: Mdm2 or Mdmx (also called Mdm4) breast cancer (BrCa), frequency mutations varies markedly between different subtypes, with basal-like BrCas bearing a high mutations, whereas...
The p53 regulatory network is critically involved in preventing the initiation of cancer. In unstressed cells, maintained at low levels and largely inactive, mainly through action its two essential negative regulators, HDM2 HDMX. abundance activity are up-regulated response to various stresses, including DNA damage oncogene activation. Active initiates transcriptional transcription-independent programs that result cell cycle arrest, cellular senescence, or apoptosis. also activates...
Mutation of the key tumour suppressor p53 defines a transition in progression towards aggressive and metastatic breast cancer (BC) with poorest outcome. Specifically, mutation frequency exceeds 50% triple-negative BC. Key regulators mutant that facilitate its oncogenic functions are potential therapeutic targets. We report here MDM4 protein is frequently abundant context basal-like BC samples. Importantly, we show plays critical role proliferation these cells. demonstrate conditional...
// Renier Heijkants 1 , Karen Willekens 2, 3 Mark Schoonderwoerd 4 Amina Teunisse Maaike Nieveen Enrico Radaelli 5 Luuk Hawinkels Jean-Christophe Marine and Aart Jochemsen Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands 2 Laboratory for Cancer VIB Center Leuven, Belgium Oncology, KU Gastroenterology-Hepatology, Mouse Histopathology Core Facility, the Biology Disease, Correspondence to: Jochemsen, email: A.G.Jochemsen@lumc.nl Keywords:...
Malignant melanoma of the conjunctiva (CM) is an uncommon but potentially deadly disorder. Many malignancies show increased activity epigenetic modifier enhancer zeste homolog 2 (EZH2). We studied whether EZH2 expressed in CM, and it may be a target for therapy this malignancy. Immunohistochemical analysis showed that protein expression was absent normal conjunctival melanocytes primary acquired melanosis, while highly 13 (50%) 26 CM seven (88%) eight lymph node metastases. Increased...
Background Immunotherapy of cancer is successful but tumor regression often incomplete and followed by escape. Understanding the mechanisms underlying this acquired resistance will aid development more effective treatments. Methods We exploited a mouse model where tumor-specific therapeutic vaccination results in regression, local recurrence resistance. In depth studies on systemic, intrinsic changes were performed with flow mass cytometry, immunohistochemistry, transcriptomics several...
Targeting the MAPK signaling pathway has transformed treatment of metastatic melanoma. CRISPR-Cas9 genetic screens provide a genome-wide approach to uncover novel dependencies that might serve as therapeutic targets. Here, we analyzed recently reported comparing data from 28 melanoma cell lines and 313 other tumor types in order identify fitness genes related We found an average 1,494 each line. identified 33 genes, inactivation which specifically reduced This set type-specific includes...
Reactivation of dormant cancer cells can lead to relapse, metastasis, and patient death. Dormancy is a nonproliferative state linked late relapse No targeted therapy currently available eliminate cells, highlighting the need for deeper understanding reliable models. Here, we thoroughly characterize D2.OR ZR-75-1, proliferative D2A1 breast cell line models in vivo and/or vitro, assess if there overlap between senescent phenotype. We show that but not become liver an immunocompetent model. In...
TP53 gene mutation is associated with poor prognosis in breast cancer, but additional biomarkers that can further refine the impact of p53 pathway are needed to achieve clinical utility. In this study, we evaluated a role for HDMX-S/FL ratio as one such biomarker, based on its association other suppressor mutations confer worse sarcomas, another type cancer surveilled by p53. We found interacted mutational status significantly improve prognostic capability patients cancer. This biomarker...