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.
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.
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.
Osorio FG, Rosendahl Huber A, Oka R, Verheul M, Patel SH, Hasaart K, de la Fonteijne L, Varela I, Camargo F, van Boxtel R. Somatic mutations reveal lineage relationships and age-related mutagenesis in human hematopoiesis. (2018) Cell Reports 25:2308-2316. PMID: 30485801 PubMed PMID: 30485801Jager M, Blokzijl F, Sasselli V, Boymans S, Janssen R, Besselink N, Clevers H, van Boxtel R*, Cuppen E*. Measuring mutation accumulation in single human adult stem cells by whole-genome sequencing of organoid cultures. (2018) Nature Protocols 13:59–78. PubMed PMID: 29215633
Drost J*, van Boxtel R*, Blokzijl F, Mizutani T, Sasaki N, Sasselli V, de Ligt J, Behjati S, Grolleman JE, van Wezel T, Nik-Zainal S, Kuiper RP, Cuppen E, Clevers H. Use of CRISPR-modified human stem cell organoids to study the origin of mutational signatures in cancer. (2017) Science 358:234-238. PubMed PMID: 28912133
Blokzijl F, de Ligt J, Jager M, Sasselli V, Roerink S, Sasaki N, Huch M, Boymans S, Kuijk E, Prins P, Nijman IJ, Martincorena I, Mokry M, Wiegerinck CL, Middendorp S, Sato T, Schwank G, Nieuwenhuis EE, Verstegen MM, van der Laan LJ, de Jonge J, IJzermans JN, Vries RG, van de Wetering M, Stratton MR, Clevers H, Cuppen E, van Boxtel R. Tissue-specific mutation accumulation in human adult stem cells during life. (2016) Nature 538:260-264. PubMed PMID: 27698416
Huch M*, Gehart H*, van Boxtel R*, Hamer K, Blokzijl F, Verstegen MM, Ellis E, van Wenum M, Fuchs SA, de Ligt J, van de Wetering M, Sasaki N, Boers SJ, Kemperman H, de Jonge J, Ijzermans JN, Nieuwenhuis EE, Hoekstra R, Strom S, Vries RR, van der Laan LJ, Cuppen E, Clevers H. Long-term culture of genome-stable bipotent stem cells from adult human liver. (2015) Cell 160:299-312. PubMed PMID: 25533785
van Boxtel R, Gomez-Puerto C, Mokry M, Eijkelenboom A, van der Vos KE, Nieuwenhuis EE, Burgering BM, Lam EW, Coffer PJ. FOXP1 acts through a negative feedback loop to suppress FOXO-induced apoptosis. (2013) Cell Death & Differentiation 20:1219-1229. PubMed PMID: 23832113