ORCID Profile
0000-0001-8677-3423
Current Organisations
Shanghai Jiao Tong University
,
Netherlands Cancer Institute
,
Oncosence
,
Agendia BV
,
Universiteit Utrecht
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Springer Science and Business Media LLC
Date: 19-02-2012
DOI: 10.1038/NM.2619
Abstract: In advanced cancer, including glioblastoma, the transforming growth factor β (TGF-β) pathway acts as an oncogenic factor and is considered to be a therapeutic target. Using a functional RNAi screen, we identified the deubiquitinating enzyme ubiquitin-specific peptidase 15 (USP15) as a key component of the TGF-β signaling pathway. USP15 binds to the SMAD7-SMAD specific E3 ubiquitin protein ligase 2 (SMURF2) complex and deubiquitinates and stabilizes type I TGF-β receptor (TβR-I), leading to an enhanced TGF-β signal. High expression of USP15 correlates with high TGF-β activity, and the USP15 gene is found lified in glioblastoma, breast and ovarian cancer. USP15 lification confers poor prognosis in in iduals with glioblastoma. Downregulation or inhibition of USP15 in a patient-derived orthotopic mouse model of glioblastoma decreases TGF-β activity. Moreover, depletion of USP15 decreases the oncogenic capacity of patient-derived glioma-initiating cells due to the repression of TGF-β signaling. Our results show that USP15 regulates the TGF-β pathway and is a key factor in glioblastoma pathogenesis.
Publisher: Public Library of Science (PLoS)
Date: 07-12-2007
Publisher: Wiley
Date: 12-10-2012
DOI: 10.1002/PATH.4092
Publisher: Springer Science and Business Media LLC
Date: 29-02-2016
DOI: 10.1038/ONC.2016.32
Publisher: Proceedings of the National Academy of Sciences
Date: 04-04-2006
Abstract: The Wnt-signaling cascade is required for several crucial steps during early embryogenesis, and its activity is modulated by various agonists and antagonists to provide spatiotemporal-specific signaling. Naked cuticle is a Wnt antagonist that itself is induced by Wnt signaling to keep Wnt signaling in check. Little is known about the regulation of this antagonist. We have recently shown that the protein phosphatase 2A regulatory subunit PR72 is required for the inhibitory effect of Naked cuticle on Wnt signaling. In the present study, we show that PR130, which has an N terminus that differs from that of PR72 but shares the same C terminus, also interacts with Naked cuticle but instead functions as an activator of the Wnt-signaling pathway, both in cell culture and during development. We find that PR130 modulates Wnt signal transduction by restricting the ability of Naked cuticle to function as a Wnt inhibitor. Our data establish PR130 as a modulator of the Wnt-signaling pathway and suggest a mechanism of Wnt signal regulation in which the inhibitory activity of Naked cuticle is determined by the relative level of expression of two transcripts of the same protein phosphatase 2A regulatory subunit.
Publisher: Elsevier BV
Date: 2009
DOI: 10.1016/J.BBCAN.2008.05.005
Abstract: The serine/threonine protein phosphatase (PP2A) is a trimeric holoenzyme that plays an integral role in the regulation of a number of major signaling pathways whose deregulation can contribute to cancer. The specificity and activity of PP2A are highly regulated through the interaction of a family of regulatory B subunits with the substrates. Accumulating evidence indicates that PP2A acts as a tumor suppressor. In this review we summarize the known effects of specific PP2A holoenzymes and their roles in cancer relevant pathways. In particular we highlight PP2A function in the regulation of MAPK and Wnt signaling.
Publisher: Springer Science and Business Media LLC
Date: 12-04-2004
Publisher: Springer Science and Business Media LLC
Date: 03-2011
DOI: 10.1038/NM.2311
Abstract: The gradual shift from cytotoxic drugs to highly selective, targeted therapeutic agents for cancer requires a parallel effort to characterize cancers at the molecular level to guide the choice of therapy for the in idual patient. Here we review the genomic technologies that can be used to develop these drug response indicators, or biomarkers. We also discuss hurdles in their development and the implementation of biomarkers in clinical practice.
Publisher: Springer Science and Business Media LLC
Date: 05-01-2016
DOI: 10.1038/SREP18517
Abstract: Invasive lobular carcinoma (ILC) is the second most frequently occurring histological breast cancer subtype after invasive ductal carcinoma (IDC), accounting for around 10% of all breast cancers. The molecular processes that drive the development of ILC are still largely unknown. We have performed a comprehensive genomic, transcriptomic and proteomic analysis of a large ILC patient cohort and present here an integrated molecular portrait of ILC. Mutations in CDH1 and in the PI3K pathway are the most frequent molecular alterations in ILC. We identified two main subtypes of ILCs: (i) an immune related subtype with mRNA up-regulation of PD-L1, PD-1 and CTLA-4 and greater sensitivity to DNA-damaging agents in representative cell line models (ii) a hormone related subtype, associated with Epithelial to Mesenchymal Transition (EMT) and gain of chromosomes 1q and 8q and loss of chromosome 11q. Using the somatic mutation rate and eIF4B protein level, we identified three groups with different clinical outcomes, including a group with extremely good prognosis. We provide a comprehensive overview of the molecular alterations driving ILC and have explored links with therapy response. This molecular characterization may help to tailor treatment of ILC through the application of specific targeted, chemo- and/or immune-therapies.
Publisher: Wiley
Date: 07-05-2015
Publisher: Wiley
Date: 07-06-2013
DOI: 10.1002/PATH.4209
Abstract: Oncogenic fusion genes that involve kinases have proven to be effective targets for therapy in a wide range of cancers. Unfortunately, the diagnostic approaches required to identify these events are struggling to keep pace with the erse array of genetic alterations that occur in cancer. Diagnostic screening in solid tumours is particularly challenging, as many fusion genes occur with a low frequency. To overcome these limitations, we developed a capture enrichment strategy to enable high-throughput transcript sequencing of the human kinome. This approach provides a global overview of kinase fusion events, irrespective of the identity of the fusion partner. To demonstrate the utility of this system, we profiled 100 non-small cell lung cancers and identified numerous genetic alterations impacting fibroblast growth factor receptor 3 (FGFR3) in lung squamous cell carcinoma and a novel ALK fusion partner in lung adenocarcinoma.
Publisher: Elsevier BV
Date: 09-2005
DOI: 10.1016/J.CELL.2005.07.003
Abstract: Retinoic acid (RA) induces proliferation arrest, differentiation, and apoptosis, and defects in retinoic acid receptor (RAR) signaling have been implicated in cancer. The human tumor antigen PRAME is overexpressed in a variety of cancers, but its function has remained unclear. We identify here PRAME as a dominant repressor of RAR signaling. PRAME binds to RAR in the presence of RA, preventing ligand-induced receptor activation and target gene transcription through recruitment of Polycomb proteins. PRAME is present at RAR target promoters and inhibits RA-induced differentiation, growth arrest, and apoptosis. Conversely, knockdown of PRAME expression by RNA interference in RA-resistant human melanoma restores RAR signaling and reinstates sensitivity to the antiproliferative effects of RA in vitro and in vivo. Our data suggest that overexpression of PRAME frequently observed in human cancers confers growth or survival advantages by antagonizing RAR signaling.
Publisher: Massachusetts Medical Society
Date: 25-08-2016
Publisher: Oxford University Press (OUP)
Date: 13-07-2012
DOI: 10.1093/BIOINFORMATICS/BTS448
Abstract: Motivation: Target enrichment, also referred to as DNA capture, provides an effective way to focus sequencing efforts on a genomic region of interest. Capture data are typically used to detect single-nucleotide variants. It can also be used to detect copy number alterations, which is particularly useful in the context of cancer, where such changes occur frequently. In copy number analysis, it is a common practice to determine log-ratios between test and control s les, but this approach results in a loss of information as it disregards the total coverage or intensity at a locus. Results: We modeled the coverage or intensity of the test s le as a linear function of the control s le. This regression approach is able to deal with regions that are completely deleted, which are problematic for methods that use log-ratios. To demonstrate the utility of our approach, we used capture data to determine copy number for a set of 600 genes in a panel of nine breast cancer cell lines. We found high concordance between our results and those generated using a single-nucleotide polymorphsim genotyping platform. When we compared our results with other log-ratio-based methods, including ExomeCNV, we found that our approach produced better overall correlation with SNP data. Availability: The algorithm is implemented in C and R and the code can be downloaded from bioinformatics.nki.nl/ocs/ Contact: l.wessels@nki.nl Supplementary information: Supplementary data are available at Bioinformatics online.
Publisher: Elsevier BV
Date: 08-2016
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-04-2015
Abstract: We investigated whether mutations in the gene encoding the phosphatidylinositol 3-kinase (PI3K) catalytic subunit (PIK3CA) correlates with response to neoadjuvant human epidermal growth factor receptor 2 (HER2) –targeted therapies in patients with breast cancer. Baseline tissue biopsies were available from patients with HER2-positive early breast cancer who were enrolled onto the Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial (NeoALTTO). Activating mutations in PIK3CA were identified using mass spectrometry–based genotyping. PIK3CA mutations were identified in 23% of HER2-positive breast tumors, and these mutations were associated with poorer outcome in all of the treatment arms. Patients treated with a combination of trastuzumab and lapatinib who had wild-type PIK3CA obtained a total pathologic complete response (pCR) rate of 53.1%, which decreased to 28.6% in patients with tumors that carried PIK3CA activating mutations (P = .012). Activating mutations in PIK3CA predicted poor pCR in patients with HER2-positive breast cancer treated with neoadjuvant therapies that target HER2. Consequently, the combination of anti-HER2 agents and PI3K inhibitors is being investigated.
Publisher: Wiley
Date: 15-02-2013
DOI: 10.1002/PATH.4152
Abstract: Diffuse gastric cancers typically present as late-stage tumours and, as a result, the 5 year survival rate is poor. Some gastric cancers are hereditary and these tend to be of the diffuse type 30-40% of hereditary diffuse gastric cancers (HDGCs) can be explained by defective germline alleles of E-cadherin (CDH1), but for the remaining families the factors driving susceptibility remain unknown. We had access to a large HDGC pedigree with no obvious mutation in CDH1, and applied exome sequencing to identify new genes involved in gastric cancer. We identified a germline truncating allele of α-E-catenin (CTNNA1) that was present in two family members with invasive diffuse gastric cancer and four in which intramucosal signet ring cells were detected as part of endoscopic surveillance. The remaining CTNNA1 allele was silenced in the two diffuse gastric cancers from the family that were available for screening, and this was also true for signet ring cells identified in endoscopic biopsies. Since α-E-catenin functions in the same complex as E-cadherin, our results call attention to the broader signalling network surrounding these proteins in HDGC. We also detected somatic mutations in one tumour and found substantial overlap with genes mutated in sporadic gastric cancer, including PIK3CA, ARID1A, MED12 and MED23.
Publisher: American Association for Cancer Research (AACR)
Date: 14-11-2008
DOI: 10.1158/0008-5472.CAN-08-1740
Abstract: Small molecule inhibitors of HER2 are clinically active in women with advanced HER2-positive breast cancer who have progressed on trastuzumab treatment. However, the effectiveness of this class of agents is limited by either primary resistance or acquired resistance. Using an unbiased genetic approach, we performed a genome wide loss-of-function short hairpin RNA screen to identify novel modulators of resistance to lapatinib, a recently approved anti-HER2 tyrosine kinase inhibitor. Here, we have identified the tumor suppressor PTEN as a modulator of lapatinib sensitivity in vitro and in vivo. In addition, we show that two dominant activating mutations in PIK3CA (E545K and H1047R), which are prevalent in breast cancer, also confer resistance to lapatinib. Furthermore, we show that phosphatidylinositol 3-kinase (PI3K)–induced lapatinib resistance can be abrogated through the use of NVP-BEZ235, a dual inhibitor of PI3K/mTOR. Our data show that deregulation of the PI3K pathway, either through loss-of-function mutations in PTEN or dominant activating mutations in PIK3CA, leads to lapatinib resistance, which can be effectively reversed by NVP-BEZ235. [Cancer Res 2008 (22):9221–30]
Publisher: Wiley
Date: 20-11-2013
DOI: 10.1002/IJC.28387
Publisher: Impact Journals, LLC
Date: 22-11-2015
Location: United States of America
Location: United States of America
No related grants have been discovered for Rene Bernards.