Research Group VOEST
Faculty of Medicine, University Medical Centre Utrecht, Dept. of Medical OncologyContact: Prof. dr. Emile Voest
E-mail: e.e.voest@umcutrecht.nl
Website: http://www.umcutrecht.nl/subsite/oncology/Research-groups/Voest/
General research focus: Microenvironment, angiogenesis, and mutations in cancer
Our general research focus consists of two main parts:
1) understanding the cancer-host interaction through analysis of the tumor microenvironment with emphasis on endothelial and mesenchymal progenitor cells, and
2) understanding the tumor cell machinery with emphasis on genetic changes.
Together, these approaches should lead to the personalized treatment of cancer using targeted therapies.
Research line 1: Evaluation of the role of bone marrow-derived cells in tumor growth and metastasis.
BACKGROUND
Tumors actively generate their micro-environment by recruiting various types of bone marrow-derived progenitor cells (BMDC). Different lineages of supporting progenitor cells can be released from the bone marrow and potentially support tumor growth, angiogenesis and metastasis formation. It was recently shown that chemotherapy can increase this release of various BMDC in an immediate “seek and repair” manner, presumably in order to support tissue regeneration, resulting in a diminished anti-tumor effect of the chemotherapy. Main players in this process are endothelial progenitor cells (EPC), which contribute to neo-angiogenesis, haematopoietic progenitor cells (HPC), which form a pre-metastatic niche and mesenchymal progenitor cells (MPC), which contribute to the stroma of developing tumors.
EXPERIMENTAL APPROACH
In this research line we have two major projects: the first focuses on the role of chemotherapy-induced release of progenitor cells on the formation and outgrowth of metastasis. The second project focuses on the role of these cells in the development of resistance to chemotherapy.
For the first project we use an orthotopic breast cancer model that spontaneously metastasizes and two different lung metastasis models using intravenous injections of the tumor cells. For the second model we use two different murine subcutaneous tumor models and a xenograft model with human breast cancer cells. In both projects we use different types of clinically relevant chemotherapies and various intervention strategies mainly targeting growth factors or their receptors, e.g. anti-VEGF therapy. Furthermore, we use bioluminescence imaging techniques, GFP-positive bone marrow and fluorescent tumor cells for confocal imaging, immunohistochemistry and flowcytometry analysis of blood and tissue.
Besides these mice models we collect patient material to translate our findings into the clinic.
CLINICAL RELEVANCE
Understanding the host response to cancer and anti-cancer treatment will facilitate new approaches to further improve treatment outcome.
Techniques: Mouse cancer models, tissue culture, immunohistochemistry, confocal microscopy, flow cytometry, intervention strategies.
Research line 2: Mutational analysis of the tumor genome.
BACKGROUND
This project aims to investigate how the mutation profile of a metastasis differs from the primary tumor and correlate these mutational profiles to clinical characteristics. The very recent advent of Next Generation Sequencing (NGS) technology has provided the technological basis to approach this problem.
This project makes use of our extensive experience with two NGS platforms to scrutinize (predicted) cancer-associated genes for mutations that could confer a direct, oligogenic, or modifier effect, generating new diagnostic and therapeutic predictive applications.
GENOME SEQUENCING PROCEDURE
We have developed and validated a Genome Sequencing Procedure (GSP) to integrate NGS technology in our laboratory.
We have optimized: (A) laser capture microdissection of tumor tissue; (B) DNA-isolation from tumor cells; (C) the development of a ‘cancer genome’ (1200 genes, including identified cancer candidate (CAN) genes , genes encoding all 518 kinases and other genes particularly related to important signaling pathways involved in anti-cancer treatment; (D) capturing this custom-made ‘cancer genome’ from whole genome tumor DNA using a commercially (Agilent) available microarray, followed by next-generation sequencing by SOLiD System 3 (Applied Biosystems); (E) bioinformatic analysis of the NGS data, and (F) functional analysis of the mutational profiles.
In conclusion, in our lab, conditions are created for an optimal and selective sequencing procedure of patient tumor tissue with high throughput capacity.
EXPERIMENTAL APPROACH
We have generated an electronic patient database with relevant clinical information from a cohort of well-characterized patients with metastasized colorectal, breast or kidney cancer. This cohort will be used for NGS on a large set of genes (> 1200) isolated from the primary tumor and associated metastasis. Identified mutations will be re-sequenced by conventional Sanger techniques to establish the acquired variant. Mutation profiles will be compared between primary tumor and metastasis to obtain knowledge of tumor evolution. Mutation profiles will be associated with survival data and therapeutic responsiveness to interrogate their predictive potential. Novel identified mutations need to be functionally confirmed to discern pathogenic from benign variants. It is anticipated that new research questions relevant to molecular cancer genetics will be generated by this process. Finally, the obtained mutational data with related clinical relevant information will be integrated with knowledge from other international available sequencing sources to come to a systems model for explaining and predicting phenotypes, their variability and the prediction of therapeutic responsiveness.
CLINICAL RELEVANCE
This project will pave the way towards ‘personalized targeted therapy’.
Techniques: DNA analysis, next generation sequencing platforms, systems biology, pathology
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