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Holstege group

Studying gene expression is pivotal for understanding cellular systems in health and in disease. We are internationally recognized pioneers of systems approaches to transcription regulation and successfully combine genomics with bioinformatics, genetics, molecular and cellular biology, biochemistry and single-cell approaches. We answer fundamental questions about the molecular mechanisms of gene regulation, including epigenetics, and directly address clinical challenges such as patient stratification and treatment response.

PI: Prof.dr. Frank Holstege
Single-cell genomics:

“Solving pediatric cancer one cell at a time.” The step from single gene to genomics approaches transformed the Life Sciences in the early part of this millennium. Single cell genomics is likely to be equally transformative. This is especially true for cancer research where it has been extremely difficult to study tumor heterogeneity - until the advent of single cell genomics that is. In collaboration with the Van Oudenaarden group, we have set up relatively cheap and robust single cell mRNA sequencing technology, along with an appropriate data processing pipeline. Often in collaboration with other groups, this is being applied across a spectrum of different research questions derived from a variety of pediatric cancers. These questions deal with developmental biology, determining the cell type of origin for example, to the composition of tumor stroma, identifying tumor-invasive immune cells, investigating tumor clonality and predicting individual treatment response.

"Previous experience in our subject areas is not essential for a successful application to join our group. Previous ambition and excellence in something that you are passionate about is." Prof.dr. Frank Holstege - PI
Soft tissue sarcomas:

In children, soft tissue sarcomas have been relatively poorly studied because they consist of many different types of cancer that individually do not occur frequently. As with many other cancers, a major bottle-neck is the availability of appropriate cellular models to investigate tumor development and new treatment options. We have focused on setting up so-called tumor organoid technology in order to culture genetically stable “tumoroids”: tumor cells directly derived from primary tumors and grown under specific laboratory conditions. This is successfully working for rhabdomyosarcomas as well as for a few other soft tissue sarcoma types. Development of protocols for other soft tissue sarcomas is underway. The tumoroids that we already have in culture are now being used for drug screens, for genetic (CRISPR-Cas9) screens to find synthetic lethal pathways and the causes of treatment resistance, as well as for analysis of transcription regulation mechanisms to determine the prime tumor-driving targets of oncogenic transcription-, chromatin- and epigenetic-factors.

 

Pediatric cancer genomics:

An ever-growing array of genomics technologies is changing the molecular diagnosis of cancer, as well as contributing to research into cancer etiology. In collaboration with molecular pathology (Tops) and the computation group (Kemmeren), we are establishing a number of standard genomics technologies that we aim to apply to all new patients. Some of these are part of routine diagnosis. Others are more experimental, for which informed consent will be first asked. The technologies encompass whole genome sequencing (WGS), whole exome sequencing (WES), panel WES, RNA sequencing and DNA methylation analysis. These technologies will be tested side-by-side for a fixed period, after which an assessment will be made to decide which to continue and for which purpose.
 

Flow cytometry core facility

Flow cytometry and Fluorescence Activated Cell Sorting (FACS) are pivotal technologies for a large number of different research projects. The flow cytometry core facility (FCCF) at the Princess Máxima Centre makes state-of-the-art cytometry technology as well as expert support available to all research projects that require this. The current machine-park consists of an Astrios EQ 23-colour sorter, a Sony 6-colour sorter, a Cytoflex LX 21-colour analyser, a Cytoflex S 13-colour analyser and a MacsQuant 8-colour analyser. Various levels of support and training are offered for these machines.

For details get in touch with Tomasz Poplonski: T.M.Poplonski-2@prinsesmaximacentrum.nl

 



Members of the Holstege group