A5085355842- Epigenetics and DNA Methylation
- CRISPR and Genetic Engineering
- BRCA gene mutations in cancer
- Virus-based gene therapy research
- DNA Repair Mechanisms
- RNA modifications and cancer
- Cancer Cells and Metastasis
- Fibroblast Growth Factor Research
- Lung Cancer Research Studies
- Immune cells in cancer
- CAR-T cell therapy research
- Hippo pathway signaling and YAP/TAZ
- Cancer Research and Treatments
- Health, Environment, Cognitive Aging
- Nutrition, Genetics, and Disease
- Cancer Genomics and Diagnostics
- Single-cell and spatial transcriptomics
- Monoclonal and Polyclonal Antibodies Research
- PI3K/AKT/mTOR signaling in cancer
- Phagocytosis and Immune Regulation
- Histone Deacetylase Inhibitors Research
- PARP inhibition in cancer therapy
- Immune Cell Function and Interaction
- Cancer-related molecular mechanisms research
- Lymphoma Diagnosis and Treatment
The Netherlands Cancer Institute
2016-2025
Rockefeller University
2018
Oncode Institute
2016
Erasmus MC Cancer Institute
2016
Large-scale sequencing studies are rapidly identifying putative oncogenic mutations in human tumors. However, discrimination between passenger and driver events tumorigenesis remains challenging requires vivo validation reliable animal models of cancer. In this study, we describe a novel strategy for candidate tumor suppressors implicated invasive lobular breast carcinoma (ILC), which is hallmarked by loss the cell-cell adhesion molecule E-cadherin. We an approach to model ILC intraductal...
Abstract Somatic hotspot mutations and structural amplifications fusions that affect fibroblast growth factor receptor 2 (encoded by FGFR2 ) occur in multiple types of cancer 1 . However, clinical responses to FGFR inhibitors have remained variable 1–9 , emphasizing the need better understand which alterations are oncogenic therapeutically targetable. Here we apply transposon-based screening 10,11 tumour modelling mice 12,13 find truncation exon 18 (E18) Fgfr2 is a potent driver mutation....
Kras-driven non–small-cell lung cancers (NSCLCs) are a leading cause of death with limited therapeutic options. Many NSCLCs exhibit high levels Ezh2, the enzymatic subunit polycomb repressive complex 2 (PRC2). We tested Ezh2 inhibitors as single agents or before chemotherapy in mice orthotopic NSCLC grafts, which homogeneously express Ezh2. These tumors display sensitivity to EZH2 inhibition by GSK126 but also amplify an inflammatory program involving signaling through NF-κB and genes...
Breast cancer (BC) is a heterogeneous disease with diverse morphological and molecular subtypes. Preclinical models that recapitulate the heterogeneity of human BC are needed to advance our fundamental understanding what makes an aggressive disease. To study mechanisms underlying progression, we generated orthotopic cell line-derived xenograft (CDX) from 20 different lines using both mammary intraductal (MIND) injections fat-pad transplantations (FPT). The resulting MIND-CDX FPT-CDX covered...
The enzyme glutaminyl-peptide cyclotransferase-like protein (QPCTL) catalyzes the formation of pyroglutamate residues at NH2-terminus proteins, thereby influencing their biological properties. A number studies have implicated QPCTL in regulation chemokine stability. Furthermore, activity has recently been shown to be critical for high-affinity SIRPα binding site CD47 "don't-eat-me" protein. Based on latter data, interference with —and hence maturation—may proposed as a means promote...
Abstract Crosslink repair depends on the Fanconi anemia pathway and translesion synthesis polymerases that replicate over unhooked crosslinks. Translesion is regulated via ubiquitination of PCNA, independently polymerase REV1. The division labor between PCNA-ubiquitination REV1 in interstrand crosslink unclear. Inhibition either these pathways has been proposed as a strategy to increase cytotoxicity platinating agents cancer treatment. Here, we defined importance for DNA mammalian ICL...
Abstract Background The majority of BRCA1 -mutant breast cancers are characterized by a triple-negative phenotype and basal-like molecular subtype, associated with aggressive clinical behavior. Current treatment options limited, highlighting the need for development novel targeted therapies this tumor subtype. Methods Our group previously showed that EZH2 is functionally relevant in BRCA1-deficient tumors blocking enzymatic activity could be potent strategy. To validate role as therapeutic...
Targeting the PI3K-AKT-mTOR pathway is a promising therapeutic strategy for breast cancer treatment. However, low response rates and development of resistance to inhibitors remain major clinical challenges. Here, we show that MYC activation drives mTOR (mTORi) in cancer. Multiomic profiling mouse invasive lobular carcinoma (ILC) tumors revealed recurrent Myc amplifications acquired mTORi AZD8055. was associated with biological processes linked counteracted mTORi-induced translation...
Abstract Male breast cancer is a rare disease that largely overlooked and clinically regarded to recapitulate female biology. The worse overall outcome for male patients compared females, however, underscores inadequate management sex-based divergence in To gain more insight into biology pathology, we used mouse models of triple-negative 3D whole-mount confocal imaging techniques evaluate both vivo ex mammary gland development, tumor formation, hormone signaling dependence. Our results show...
Abstract Polycomb repressive complexes (PRC) are frequently implicated in human cancer acting either as oncogenes or tumor suppressors. Here we show that PRC2 is a critical regulator of Kras-driven non-small-cell lung (NSCLC) progression. Modulation by Ezh2 overexpression Eed deletion enhances adenomagenesis and inflammation, respectively. Eed-loss-driven inflammation leads to massive macrophage recruitment marked decline tissue function. Additional Trp53 inactivation activates cell...
Abstract Invasive lobular carcinoma (ILC) is the second most common breast cancer subtype, accounting for 5% to 15% of tumors.The majority ILCs are characterized by complete loss cell adhesion protein E-cadherin encoded CDH1 gene. However, WAPcre;Cdh1F/F mice with mammary gland-specific do not develop ILC, unless coupled additional disruption a tumor suppressor gene, like Pten or Trp53. Compound mutant lesions that closely resemble human disease in terms histology and invasivity. genome-wide...
Abstract Kras mutant non-small cell lung cancer (NSCLC) is a leading cause of death but has limited therapeutic options. We investigated the impact Polycomb repressive complex 2 (PRC2) inhibitors as single agent or neoadjuvant treatment for subsequent anti-inflammatory therapy. Using orthotopic grafts, we show that cells highly expressing PRC2 enzymatic component Ezh2 display sensitivity to its inhibition. inhibition leads transcriptional amplification an inflammatory program involving...
Abstract Large-scale sequencing studies are rapidly identifying putative oncogenic mutations in human tumors. However, discrimination between passenger and driver events tumorigenesis remains challenging requires vivo validation reliable animal models of cancer. For these reasons, new technologies needed to expand the genetic toolbox cancer biologists allow a more rapid systematic interrogation gene perturbations. In this regard, advent CRISPR/Cas9 for somatic genome editing has already...
Background The majority of BRCA1-mutant breast cancers are characterized by a triple-negative phenotype and basal-like molecular subtype, associated with aggressive clinical behavior. Current treatment options limited, highlighting the need for development novel targeted therapies this tumor subtype.
Abstract Background: The majority of BRCA1 -mutant breast cancers are characterized by a triple-negative phenotype (TNBC) and basal-like molecular subtype, associated with aggressive clinical behavior. Current treatment options limited, highlighting the need for development novel targeted therapies this tumor subtype. Methods: Our group previously showed that EZH2 is functionally relevant in BRCA1-deficient tumors blocking enzymatic activity could be potent strategy. To validate role as...