Van Boxtel Lab

"To beat cancer, we need to know how it starts."

About
In 2017, Ruben van Boxtel started his lab at the Princess Máxima Center for pediatric oncology. Today we have 20 people in our group working on determining the mechanisms and rate-limiting steps underlying the genesis of childhood cancers.


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Why do certain individuals develop cancer and others don’t? And why do children get cancer? Our vision is that by studying mutations in normal cells, we obtain insight into the etiology of cancer. We think this knowledge is crucial to improve cancer diagnostics and treatment, as well as for developing preventive strategies.

On the origin of cancer: studying somatic evolution in normal tissues

Identifying the rate limiting steps of cancer initiation in human tissues is challenging as many factors can play a role. The mutations in the genomes of cells can serve as an archive of their life history. We aim to decode these archives in order to pinpoint the initiation of cancer and identify causal processes in human tissues. To study the etiology of cancer, we have 3 research themes in our lab.

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Theme 1: Tissue-specific mutation accumulation in human stem cells

Organ-specific cancer incidence varies significantly throughout the human body, which cannot be solely explained by different exposures to mutagenic environmental. Adult stem cells are likely the cellular targets for accumulation of pre-cancerous successive oncogenic hits, which eventually can give rise to tumor development, owing to their life-long capacity to propagate mutations to both self-renewing progeny and downstream progenitors. We aim to identify and study the mutational processes that are active in adult stem cells of various organs and precede oncogenic transformation.

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Theme 2: Tracking the origin of cancer

DNA is the largest biomolecule in the cells, which unlike other biomolecules is irreplaceable. The processes causing mutations leave characteristic patterns in the DNA, which can serve as a functional readout of mutagenic and/or DNA repair activity. In addition, phylogenetic relationships between different cells of the same individual can be exploited measure clonal dynamics within tissues. We aim to identify and study the mechanisms underlying characteristic mutation patterns in cancers as well as use mutations to retrospectively trace the cellular origin of cancer.

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Theme 3: The etiology of therapy-related malignancies in cancer survivors

Most chemotherapeutic drugs act by fatally damaging the DNA or blocking the replication thereof. However, noncancerous cells are also damaged by treatment, which can result in the accumulation of DNA mutations in normal tissues with potentially adverse effects later in life, such as novel malignancies. Our goal is to study the mutational effects of cancer treatment in normal tissues of children in order to develop novel treatment strategies aimed at minimizing or preventing adverse late effects.

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Ruben van Boxtel

Principal Investigator

Annemarie Rietman

Scientific Research Coordinator

Friederike Meyer - Wentrup

Clinical Co-PI

Mark van Roosmalen

Bioinformatician

Diego Montiel Gonzalez

Bioinformatician

Rico Hagelaar

Bioinformatician

Mark Verheul

Technician

Niels Groenen

Technician

Laurianne Trabut

Technician

Sjors Middelkamp

Postdoc

Joske Ubels

Postdoc

Inge van der Werf

Postdoc

Freek Manders

PhD student

Eline Bertrums

MD, PhD student

Jurrian de Kanter

PhD student

Flavia Peci

PhD student

Lucca Derks

PhD Student

Vera Poort

PhD Student

Annina Roelofsen

MSc Student

Weekend van de Wetenschap 2022

Vind hier de presentatie van Ruben tijdens het Weekend van de Wetenschap 2022.

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Jurrian de Kanter wins "CS&D best publication of the year" award

Each year, the graduate school Cancer, Stem cells and Developmental biology gives an award to the PhD student with the best publication of that year. Today, the award was given to Jurrian de Kanter from our group for his two publications on the damaging effects of treatment in children with cancer.

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Now published in Cancer Discovery

Elevated mutational age in blood of children treated for cancer contributes to therapy-related myeloid neoplasms

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Karlijn defends her PhD thesis

"The beginning of a new life: characterising somatic mutation accumulation in fetal stem cells"

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New publication in STAR protocols!

Whole-genome sequencing and mutational analysis of human cord-blood derived stem and progenitor cells

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Proefdiervrij Venture Challenge

During a 3 months-long program six teams were guided through setting up a venture plan, which takes an animal free scientific breakthrough in the life sciences and transformed it into a solid business case.

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Axel Rosendahl Huber obtains his PhD degree

Today our PhD student Axel Rosendahl Huber successfully defended his thesis: Mapping mutations in human cells - How extrinsic agents and aging alter the genetic code

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Chemotherapy increases the mutation burden of normal blood cells in cancer survivors. Only few drugs damage the DNA directly, while in most patients, chemotherapy-induced mutations are caused by processes similar to those present during normal aging. Cancer Discovery 2022

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Antiviral treatment with ganciclovir causes a unique mutational signature in stem cells of human transplant recipients. This signature was also found in therapy-related cancers and can cause cancer driver mutations. Cell Stem Cell 2021

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In some children with acute myeloid leukemia, cancer cells have the same amount of DNA changes as healthy blood stem cells. Here, we show that these children have a poorer chance of survival compared to children whose leukemia has an above-average number of DNA changes. This study offers insight into how this form of blood cancer can develop in children. In the future, these findings may help identify which patients have a high-risk form of the disease. Blood Cancer Discovery 2021

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Our study describes a distinct mutational signature in colorectal cancer and implies that the underlying mutational process results directly from past exposure to bacteria carrying the colibactin-producing pks pathogenicity island. Nature 2020

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Mutation accumulation during life can contribute to hematopoietic dysfunction; however, the underlying dynamics are unknown. Using mutations found in in acute myeloid leukemia, we construct a developmental lineage tree of human hematopoiesis, revealing a polyclonal architecture and providing evidence that developmental clones exhibit multipotency. Cell Reports 2018

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Here we determine genome-wide mutation patterns in human adult stem cells of the small intestine, colon and liver of human donors with ages ranging from 3 to 87 years by sequencing clonal organoid cultures derived from primary multipotent cells. Our results show that mutations accumulate steadily over time in all of the assessed tissue types, at a rate of approximately 40 novel mutations per year, despite the large variation in cancer incidence among these tissues. Nature 2016

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Link to all publications

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ERC Consolidator Grant
In January 2020, Dr. Ruben van Boxtel received a Consolildator Grant of 2 million Euro's from the European Research Council. The project started in April 2020 and will be finished in 2025.

The outline of the project is: Therapy-related malignancies are a major cause of long-term mortality among childhood cancer survivors. However, it is unclear how exposure to chemo- and/or radiotherapy early in life induces carcinogenesis.
The aim is to determine the mechanisms and rate-limiting steps underlying the genesis of second malignancies in childhood cancer survivors. For this, we will focus on studying the etiology of therapy-related myeloid malignancies (t-MNs).

Dr. van Boxtel has pioneered methods to characterize mutation accumulation in single stem cells and study clonal lineages in the human hematopoietic system. The van Boxtel lab is embedded in Europe’s largest childhood cancer center, providing the opportunity to apply our techniques to unique patient material.

In Objective 1, we will dissect the life history of t-MN and study its cellular origin. Our key question is: Was the original t-MN clone already present before chemotherapy exposure, or generated as a consequence thereof? We will address this by tracking back clonal lineages in the hematopoietic tissue of patients using the mutations present in their second cancers.

In Objective 2, we will study the mutational consequences of chemotherapy in normal hematopoietic cells of children before and after they received treatment. Our key question is: Is enhanced mutagenesis rate limiting for t-MN development? To address this, we will perform in-depth mutational analyses and in vitro validations.

In Objective 3, we will determine phenotypic effects of chemotherapy on population dynamics of blood. Our key question is: how does chemotherapy affect selection dynamics and clonal composition of blood? To address this, we will integrate clonal histories and lineage contributions using somatically acquired mutations. Our unique methodology and anticipated novel insights will not contribute to improved survival of children with cancer, but also to increased fundamental knowledge on the origin of cancer.

GenomeTOX
GenomeTox will be the one-stop-shop for all animal free human based genotoxicity testing. We developed a patent protected single assay, based on whole genome sequencing of primary human hematopoietic stem cells, which allows for the assessment of all types of genotoxicity. Additionally, we can accurately predict the probability that the assessed compound can cause cancer driver mutations using artificial intelligence and our in vitro data as a training dataset.

Overview of the GenomeTOX pipeline
GenomeTOX team:

  • Annemarie Rietman, PhD, CEO, (Wageningen University, VitalNext b.v., Princess Máxima Center) has several years of experience in the management team of a start-up.
  • Ruben van Boxtel, PhD, CSO, (Hubrecht institute, Princess Máxima Center) is globally recognized for his work in the field of genome biology. 
  • Eline Bertrums, MD, Clinician, (Erasmus University, Princess Máxima Center) studies genomic aberrations and clonal evolution underlying pediatric therapy-related acute myeloid leukemia.
  • Lucca Derks, MSc, Bioinformatician, (Utrecht University, Princess Máxima Center) combines experimental and computational methods to elucidate the clonal evolution of stem cells under chemotherapy treatment.

In January 2022 we enrolled the ProefdierVrij Venture Challenge.  The Proefdiervrij Venture Challenge offered mentorship. During a 3 months-long program six teams were guided through setting up a venture plan, which takes an animal free scientific breakthrough in the life sciences and transformed it into a solid business case.  We were mentored by the team of the GameChanger Challenge BV, who have over 10 years of experience in guiding start-ups to success.

For more information please contact us by sending an e-mail to: A.Rietman@prinsesmaximacentrum.nl

Rurika Oka

Bioinformatician

Arianne Brandsma

Postdoc

Anais van Leeuwen

Technician

Axel Rosendahl Huber

PhD student

Karlijn Hasaart

PhD Student


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