Molecular Genetics: Anton Berns
Mouse Cancer Models
The aim is to utilize genetically engineered mouse models to define the (epi)genetic lesions involved in tumor initiation, progression, metastasis and tumor maintenance. These models are particularly suited to design and evaluate new intervention strategies.
We have made a significant investment in developing new mouse models for a variety of tumors, using Cre/Lox mediated switching of tumor suppressor genes and oncogenes. Both transgenesis and somatic gene transfer are employed to express Cre recombinase and other genes or shRNAs in a regulatable fashion. The methodology enables us to switch multiple oncogenes and/or tumor suppressor genes within cells in vivo at a defined time and to monitor the relevance of these genes for tumor initiation and progression. The induction of highly specific tumors within a narrow time window permits us to correlate specific genetic lesions with distinct tumor characteristics. The general picture that transpires from these studies is that the mouse cancer models show closer resemblance to the human condition when they share the same mutations. By applying sensitive in vivo imaging techniques to follow tumor growth and metastatic spread in real time in animals we not only can follow tumor development longitudinally but also monitor response to genetic and pharmacological interventions.
We focus on thoracic tumors: small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), squamous cell carcinoma (SCC) and mesothelioma. Using different sets of conditional tumor suppressor genes and oncogenes all the thoracic tumors can be induced specifically. When, for example,Rbandp53are inactivated specifically in lung, SCLC develops in nearly 100% of the mice. These tumors closely resemble human SCLC and are often heterogeneous consisting of different cell types, with either neuroendocrine or mesenchymal features. Subcutaneous grafting of each of the cell types independently gave rise to localized tumors that retained the features of the inoculated cells. However, grafting mixtures resulted in local growth as well as metastasis of the neuroendocrine cells to liver indicating that the non-neuroendocrine cells in the graft endowed the neuroendocrine cells with metastatic potential. This shows functionality of tumor cell heterogeneity. We try to uncover the underlying signaling.
An important question in our studies is the role of the cell-of-origin of these tumors. We address this by switching oncogenes and tumor suppressor genes specifically in Clara cells, Alveolar type II cells, neuroendocrine cells, basal epithelial cells of lung and in the mesothelial lining of the thoracic cavity. It appears that both the cell-of-origin and the introduced genetic lesions are critical determinants of the phenotypic characteristics of the resulting tumors. We are inquiring whether the cell of origin might also explain some of the unique features of the tumor subtypes in humans.
We are making these models more versatile by re-derivation of ES cells from them and equipping these with DNA exchange cassettes that allow us to swiftly introduced additional oncogenes, inducible shRNAs or reporters in order to test their contribution to the tumor phenotype or to the response to intervention. In this way we can also quickly evaluate the importance of putative cancer genes found by the sequencing DNA of human cancers. Furthermore, transposon-based insertional mutagenesis is conducted in these models to identify genes and pathways that strongly synergize with the driver mutations genetically inserted in these models. This will providfe us with clues what to look for in the cognate human tumors.
Parallel to these experiments we are developing protocols to establish cultures from human mesothelioma and to propagate these tumors as patient derived xenografts (PDX).
- Margriet Snoek, Ph.DAcademic Staff
- Paul KrimpenfortAcademic Staff
- Remco Nagel, Ph.DPostdoctoral Fellow
- Jitendra Badhai,Ph.DPostdoctoral Fellow
- Min Chul Kwon,Ph.DPostdoctoral Fellow
- Lorenzo Bombardelli, Ph.DPostdoctoral Fellow
- Guistina Ferone, Ph.DPostdoctoral fellow
- Hilda de Vries Ph.DPostdoctoral Fellow
- Ekaterina Semenova,Ph.DPostdoctoral Fellow
- Huub van VugtLab manager/Technical Staff
- Jan Paul LambooijTechnical Staff
- Fina van der AhéTechnical Staff
- John ZevenhovenTechnical Staff
- Jan van der VlietTechnical Staff
Margriet Snoek, Ph.D
I was trained at the University of Utrecht as a biologist with interest in immunology and tumor biology. I performed my PhD at the Netherlands Cancer Institute. My PhD thesis in the group of Dr. Peter Demant concerned the Major Histocompatibility Complex of the mouse and was entitled: Polymorphism and differences of expression of murine class I antigens on normal, tumor and DNA-manipulated cells. The focus of the Demant group slowly shifted to the genetics of tumor susceptibility in mouse models. I was involved in studies on the genetics of lung tumor susceptibility and the genetics of colon cancer susceptibility.
In the group of Prof. Dr. Anton Berns, my work as a mouse geneticist concerns amongst other things optimizing the existing mouse models for their genetic background, making speed congenic strains, mapping mutations and susceptibility genes, making genetically engineered new mouse cancer models, making constructs using the recombineering technique, and arranging the official nomenclature of our strains in consultation with the nomenclature committee of the Mouse Genome Information Database. I work together with Huub van Vugt, and we aim to assist the scientists in the Netherlands Cancer Institute with their questions on the genetics of the mouse models and offer services as making constructs, designing primers, planning of genome wide scans with microsatellites and intermediate in nomenclature requests
My main scientific interest is the tumor suppressive function of the Ink4 gene family encoding the Cdk4/6 inhibitors p15Ink4b, p16Ink4a, p18Ink4c and p19Ink4d. Since Cdk4 and Cdkn6 stimulate G1 progression by phosphorylating Rb, the primary effect of Ink4 inactivation is thought to be the loss of cell cycle control. However, apart from their role in cell cycle control recent observations suggest the implication of the Ink4 proteins in tumor cell behaviour e.g. migration and invasiveness. An important issue is if and to what extent the Ink4 genes are redundant.
In addition, I am also involved in the NKI Transgenic Facility and I am a member of the Animal Experiment Committee (DEC) of the NKI.
Remco Nagel, Ph.D
I was trained at the University of Utrecht as a molecular biologist, after which I obtained my PhD at the Netherlands Cancer Institute in the group of Prof. dr. Agami. Here my studies identified novel functions of microRNAs in various cancerous tissues. As a PostDoctoral fellow at the Vrije Universiteit Medical Center Amsterdam my work was focused on functional genetic screens to identify novel radiosensitizers for non-small cell lung cancer.
The goal of my current project is to identify combination therapies that show synergistic therapeutic effects in small cell lung cancer and mesothelioma. These synergistic interactions will be identified using loss of function screens to identify enhancers of existing therapies and exploit synthetic lethal interactions in these tumor types.
I have completed my PhD in clinical genetics from Uppsala University, Sweden and now I am working as a postdoctoral fellow at Division of Molecular Genetics, Netherlands Cancer Institute. I am particularly interested in making better mouse model and finding key driver genes in mesothelioma and small cell lung cancer (SCLC). I am employing piggyBac (PB) transposon mutagenesis in mice and integrative analysis approach in mouse tumor to find driver genes in mesothelioma and SCLC.
Min Chul Kwon,Ph.D
Min Chul is interested in elucidating molecular mechanisms of the development and metastasis of small cell lung cancer and is also working on finding novel lung cancer inducing genetic factors. He received his Ph.D. in Molecular Genetics from POSTECH in South Korea where he studied the embryonic development and organogenesis with knockout mouse models.
Lorenzo Bombardelli, Ph.D
I have been interested for a long time in mouse models of cancer and tumor microenvironment. During my PhD I worked on cell polarity and secretory pathways in pancreatic cancer and subsequently on how the crosstalk between adhesion molecules and tyrosine kinase receptors accelerates ovarian cancer dissemination.
My current work is focused on the pharmacogenomics of small-cell lung cancer (SCLC). Thanks to the transgenic models developed in the lab, I am testing new therapeutic combinations and investigate mechanisms of drug resistance in myc-driven SCLC.
Guistina Ferone, Ph.D
I gained my Ph.D. in Biochemistry and Molecular and Cellular Biology in Italy then, on July 2012, I joined the Berns lab. I consider this a great opportunity: the NKI environment is very challenging; moreover the group has extraordinary tools that make you comfortable to approach a wide range of topics. I am particularly interested in studying lung Squamous Cell Carcinoma through the generation and characterization of mouse models carrying inducible genetic lesions found in human tumors. To hit uniquely basal cells of the bronchial epithelium (cell-of-origin of SCC) I use intratracheally delivered viruses carrying Cre recombinase under specific promoters.
Hilda de Vries Ph.D
After I finished as a PhD student in the field of DNA damage, I am joining the Berns lab since 2004 and became very much interested in Malignant Mesothelioma (MM). Ever since, I created anin vitroapproach to study both normal and malignant (mouse) mesothelial cells that I now use in combination within vivomodel(s) to study the cell of origin and drug pathways. Besides this, I also work on the development of a PDX model for MM. This field of translational research gives me the opportunity to contribute to a better survival of MM patients.
I have received my PhD in Molecular Biology from Princeton University. Before joining NKI, I worked in the field of skin regeneration, inflammation and gene therapy. I am interested in developing novel lineage tracing and visualization tools to identify and track lung stem cells and tumor initiating cells using in vivo and ex vivo platforms.
Huub van Vugt
Lab manager/Technical Staff
I am a technician working with Dr. Margriet Snoek and contribute to the generation of genetically engineered mouse models for the study of genes involved in cancer.
As a lab manager I am involved in the organization of the department and do my best to create optimal conditions for the researchers to do their experiments.
Jan Paul Lambooij
I'm a technician in the group of Ton Berns since 2003. I got my article 12 in 2009.
This year, hopefully, I will help Andrej get his thesis.
Fina van der Ahé
Since 2001 I have been working as a biotechnician in the group of Prof. Anton Berns and in the Mouse clinic transgenesis unit. My job involves microinjection, genotyping, and sperm cryopreservation.
After 10 years working as a histopathology technician on a Pathology department of a hospital I made a move in the year 2000 to the research and started working at the NKI at the department of Molecular Genetics. Here I work on several projects were my expertise can be valuable to different researchers.
My job involves all kind of (immuno)histological techniques, optimizing antibodies on fresh, frozen and paraffin material. This by means of bright light microscopy or digital microscopy with a confocal laserscanner.
Jan van der Vliet
I work in the lab of Anton Berns since September 2013. In het lab I work on the different models this group has for small cell lung cancer and mesothelioma.
Research updates View All Updates
2013: Synergy-ERC grant
Together with Daniel Peeper, Jos Jonkers, and Lodewyk Wessels at the NKI and colleagues of the Wellcome Trust Sanger Institute, Anton Berns successfully applied for a prestigious synergy-ERC grant. Their program "Combination therapies for personalized medicine", provides this collaborative group with almost €15 million of funding for the coming years.
Key publications View All Publications
Mouse models for lung cancer
Mol Oncol. 2013 Apr;7(2):165-77
Kwon MC, Berns A.Link to Pubmed
Recent publications View All Publications
Stem cell CD44v isoforms promote intestinal cancer formation in Apc(min) mice downstream of Wnt signaling.
Oncogene. 2013; 1-6
Zeilstra J, Joosten SP, van Andel H, Tolg C, Berns A, Snoek M, van de Wetering M, Spaargaren M, Clevers H, Pals ST.Link to Pubmed
DCC expression by neurons regulates synaptic plasticity in the adult brain.
Cell Rep. 2013; 3: 173-85.
Horn KE, Glasgow SD, Gobert D, Bull SJ, Luk T, Girgis J, Tremblay ME, McEachern D, Bouchard JF, Haber M, Hamel E, Krimpenfort P, Murai...Link to Pubmed
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