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Van Boxtel group

We aim to study the molecular causes of childhood cancer and treatment-associated second malignancies. Our vision is that by understanding the processes that cause cancer, effective preventive therapies can be developed, diagnostics improved and choice of treatment facilitated. We focus on identifying mutational processes that drive cancer development across different tissues.

PI: Dr. Ruben van Boxtel
Theme 1: The etiology of childhood cancer

Why do children get cancer? For certain cancer types, such as leukemia, young children show a higher incidence compared with young adults. This phenomenon represents an apparent paradox, as young cells should have less somatic (oncogenic) mutations than adult cells. However, the factors underlying leukemia initiation early in life are not well understood. By characterizing mutation accumulation in pre-leukemic hematopoietic progenitors, we aim to identify the mechanisms that cause cancer initiation in children. For this, we combine stem cell culture systems with genome-wide sequencing technologies and in-depth mutational analysis, which allows us to identify and study mutational processes, selection dynamics and clonal composition of the tissue. Moreover, we have developed a strategy to explore the origin of cancer-associated mutational signatures by applying whole-genome sequencing to genetically modified human organoids using CRISPR/Cas9 technology. Ultimately, this work will facilitate the discovery of risk factors predictive for childhood cancer and contribute to improved clinical interpretation of whole-genome sequencing data.

"To beat cancer, we need to know how it starts." Dr. Ruben van Boxtel - PI
Theme 2: The consequences of cancer treatment on stem cells

What mechanisms underlie the genesis of second malignancies in childhood cancer survivors? Childhood cancer survivors have an increased risk of developing therapy-related second malignancies. To improve long-term survival of patients cured of childhood cancer, it is crucial to understand patient-related risk factors and to develop preventive therapies. For this, detailed understanding into the etiology of second cancers is necessary, which is currently lacking. We aim to determine the mechanisms underlying the genesis of second malignancies in childhood cancer survivors by characterizing mutation accumulation in precancerous cells of childhood cancer survivors who developed therapy-related malignancies. To distinguish the processes that cause cancer-initiating mutations and study clonal dynamics, we will compare the somatic mutation patterns in the normal cells with those observed in the matching therapy-related malignancy. Ultimately, the knowledge obtained by this work will allow us to identify patient-related risk factors and may ultimately contribute to novel therapies to prevent second cancer development.

Fluorescence-activated cell sorting (FACS) of hematopoietic stem cells (HSCs) from cord blood. CD34+Lin- cells are single cell index sorted into 384-well plates. Red dots indicate the sorted cells, of which ±25% is CD34+Lin-CD38-CD45RA-.

 

Strategy: DNA as a historical archive of the life of a cell

Cancers are formed by evolutionary processes acting in normal tissues. Stochastically acquired genetic and epigenetic alterations cause phenotypic diversity and evolutionary forces, such as selection and drift, subsequently shape the clonal composition of cell populations. Some genetic mutations allow cells to become independent of specific external growth factors, or insensitive to intrinsic inhibitory signals, thereby promoting uncontrolled clonal expansion. Depending on the evolutionary forces at play, this genetic diversity can eventually contribute to cancer initiation. DNA is the largest biomolecule in the cells, which unlike other biomolecules is irreplaceable. Consequently, mutations resulting from incorrectly or unrepaired DNA damage will gradually accumulate throughout the life of a cell. The complete catalogue of somatic mutations in the genome of a cell at a given time therefore serves as a historical archive, which contains signatures of mutagenic processes, selective pressure and genetic relatedness to other cells in the population. It is our mission to read this archive to understand the mechanisms that contribute to the genesis of cancer.

Suspension cell culture of AHH-1 cells, a human B lymphocyte line with almost normal and stable karyotype, which we use for gene targeting and other validation experiments.

 

 

Principle component analysis on 96 trinucleotide mutation spectra in normal stem cells and AML samples.  The colors indicate tissue type: blue dots are liver stem cells, green dots are hematopoietic stem cells, orange and brown dots are intestinal stem cells, pink dot depicts a pooled cord blood sample, red dots are adult AMLs, purple dots depict pediatric AMLs (Ma et al, 2018) and black dots depicts mutational COSMIC signatures (numbers are indicated).

 

Members of the van Boxtel group