Princess Máxima Center

Sebastiaan van Heesch is a group leader at Princess Máxima Center for Pediatric Oncology, a junior Oncode Investigator at Oncode Institute, and vice chair of the Therapeutic Vaccines workstream at Oncode Accelerator - a Dutch nation-wide program that aims to accelerate the preclinical development of cancer vaccines. Trained at the Hubrecht Institute (PhD) and the MDC Berlin (postdoc), Sebastiaan has developed a passion for RNA systems biology, proteogenomics, and cancer immunotherapy. Within the Princess Máxima Center - Europe’s largest research hospital fully dedicated to battling childhood cancer, the van Heesch lab develops and applies advanced sequencing and computational methods to find and characterize new microproteins, find new cancer mechanisms, and select those microproteins that may serve as targets for immunotherapy.

• 2023: NWO VIDI Award

• 2019: DZHK Postdoc Excellence Award

• 2015: NWO Rubicon Award

• 2015: EMBO Long-Term Fellowship

1. Hofman DA, Ruiz-Orera J, Yannuzzi I, Murugesan R, Brown A, Clauser KR, Condurat AL, van Dinter JT, Engels SAG, Goodale A, van der Lugt J, Abid T, Wang L, Zhou KN, Vogelzang J, Ligon KL, Phoenix TN, Roth JA, Root DE, Hubner N, Golub TR, Bandopadhayay P, van Heesch S, Prensner JR. Translation of non-canonical open reading frames as a cancer cell survival mechanism in childhood medulloblastoma. Molecular Cell (2024) Jan 261-276. e18. doi: https://doi.org/10.1016/j.molcel.2023.12.003

2. Prensner JR, Abelin JG, Kok LW, Clauser KR, Mudge JM, Ruiz-Orera J, Bassani-Sternberg M, Deutsch EW, van Heesch S. What can Ribo-seq, immunopeptidomics, and proteomics tell us about the non-canonical proteome? Molecular Cellular Proteomics. (2023) Aug 10:100631. doi: https://doi.org/10.1016/j.mcpro.2023.100631

3. Sandmann CL, Schulz JF, Ruiz-Orera J, Kirchner M, Ziehm M, Adami E, Marczenke M, Christ A, Liebe N, Greiner J, Schoenenberger A, Muecke MB, Liang N, Moritz RL, Sun Z, Deutsch EW, Gotthardt M, Mudge JM, Prensner JR, Willnow TE, Mertins P, van Heesch S, Hubner N. Evolutionary origins and interactomes of human, young microproteins and small peptides translated from short open reading frames. Molecular Cell (2023) Mar 16;83(6):994-1011.e18. doi: https://doi.org/10.1016/j.molcel.2023.01.023

4. Mudge JM, Ruiz-Orera J, Prensner JR, Brunet MA, Calvet F, Jungreis I, Gonzalez JM, Magrane M, Martinez TF, Schulz JF, Yang YT, Albà MM, Aspden JL, Baranov PV, Bazzini AA, Bruford E, Martin MJ, Calviello L, Carvunis AR, Chen J, Couso JP, Deutsch EW, Flicek P, Frankish A, Gerstein M, Hubner N, Ingolia NT, Kellis M, Menschaert G, Moritz RL, Ohler U, Roucou X, Saghatelian A, Weissman JS, van Heesch S. Standardized annotation of translated open reading frames. Nature Biotechnology (2022) Jul;40(7):994-999. https://doi.org/10.1038/s41587-022-01369-0

5. van Heesch S, Witte F, Schneider-Lunitz V, Schulz JF, Adami E, Faber AB, Kirchner M, Maatz H, Blachut S, Sandmann CL, Kanda M, Worth CL, Schafer S, Calviello L, Merriott R, Patone G, Hummel O, Wyler E, Obermayer B, Mücke MB, Lindberg EL, Trnka F, Memczak S, Schilling M, Felkin LE, Barton PJR, Quaife NM, Vanezis K, Diecke S, Mukai M, Mah N, Oh SJ, Kurtz A, Schramm C, Schwinge D, Sebode M, Harakalova M, Asselbergs FW, Vink A, de Weger RA, Viswanathan S, Widjaja AA, Gärtner-Rommel A, Milting H, Dos Remedios C, Knosalla C, Mertins P, Landthaler M, Vingron M, Linke WA, Seidman JG, Seidman CE, Rajewsky N, Ohler U, Cook SA, Hubner N. The Translational Landscape of the Human Heart. Cell (2019) 178(1):242-260.e29. https://doi.org/10.1016/j.cell.2019.05.010

‘Visualize the unexpected’ is the driving force behind my science.

From the start of her scientific career, Anne developed an intense passion for imaging, which she applied during her PhD in developmental biology to unveil a novel developmental scenario by which migrating cells from adjacent tissues can trigger cell fate changes in muscle stem-cells (Nature, 2011). During her postdoc, she established a method to visualize intact tissue using 3D microscopic reconstruction (Neil Lawrence prize for most creative young scientist, 2016). The power of this method in driving scientific discovery is illustrated by the first in vivo evidence for bipotent stem cells in the mammary gland (Nature, 2014, Nature cell biology, 2017) and the unexpected finding of polyploid cells during lactation (Nature Communications, 2016). Moreover, it was optimized into a rapid and easy-to-use protocol for 3D imaging of entire organs, intact tumours and organoids (Cancer Cell, 2019 -highlighted Best of Cancer Cell 2019; Nature Biotechnology 2021; Nature Protocols 2019 & Nature Protocols, 2022). Combined with a novel multicolored single-cell 3D intravital imaging technique, this technique allowed for discovering a novel population of resident macrophages essential for maintaining breast homeostasis, as well as involved in breast cancer progression (Nature Cell Biology, 2020, Nature Protocols, 2021).

In 2017, Anne was recruited as a group leader to the Princess Máxima Center for Pediatric Oncology and head of the Princess Máxima Imaging Center. In 2019, she was also appointed Oncode junior principal investigator. She built a multidisciplinary team, with experts in bioengineering, imaging and computational science and together they study cancer biology and immunotherapy treatment response. Anne is a selected next generation member of the International Society for Stem Cell Research (ISSCR), a program committee member of the European Fight Kid Cancer funding agency and a founding member of the EMBO journal catalyst program. Anne received a European Research Council (ERC) Starting Grant and KWF high risk grant for her work on pediatric brain cancer, a CGC Young PI Award to study breast cancer dynamics and a St. Baldrick’s Robert J. Arceci Innovation Award recognizing her innovative approaches to tackle paediatric cancer research. In addition, Anne is a participating PI in multiple consortia dedicated to the next generation of T cell therapies, advancing organoid technology and further developing imaging and analytical frameworks to study and guide cells in their native environment. In 2021, she received the L’Oréal-UNESCO for Woman in Science Award and is now one of the founders of ACE (Authenticity in science for Community and Excellence) to promote women in science. In 2021, she was a honorary Fellow of NIAS-KNAW (Dutch royal Academy of Arts and Sciences) for 5 months, where she developed projects related to Art and Science. She has a strong passion for engaging the public (NWO Science Communication grant, 2002) and inspiring the future generation of scientists, which she aims to achieve through unique immersive displays of her group’s 3D imaging data.

• 2022: NWO Science Communication Grant: An unexpected alliance to portray cancer.

• 2022: Horizon Europe 2021 Marie Sklodowska-Curie Actions (MSCA) Cofund co-PI. From Caterpillar to BUTTERFLY: supporting transformation of DCs in a paediatric oncology network.

• 2022: Zwaartekracht consortium grant Imagine. Innovative. Microscopy and Guidance of Cells in their naïve environment.

• 2021: ODAS Foundation, consortium grant. Identify targets to modulate CAR-T cell functionality using advanced 3D co-culture and imaging technologies: Towards better survival of pediatric BCP-ALL patients.

• 2021: KWF Consortium Grant. Targeting human cancer with the next generation of engineered immune cells: TEGs.

• 2021: L’Oréal-UNESCO for Woman in Science Award

• 2019: St. Baldrick’s Robert J. Arceci Innovation Award

• 2018: ERC starting grant Deciphering and targeting the invasive nature of Diffuse Intrinsic Pontine Glioma

• 2018: Villa Joep Optimizing neuroblastoma resection using fluorescent guided surgery

• 2018: KWF high risk Unravelling the integration of pediatric high-grade glioma in the developing brain using state-of-the-art imaging

• 2018: CGC young PI award Studying human breast cancer dynamics using multi-coloured lineage tracing

• 2017: Cancer Genomic Center member

• 2016: Lawrence Creative Prize Winner Medical Innovation Award

• 2014: Walter and Eliza Hall Research Institute Post-Doctoral Award

• 2013: Postdoctoral Fellowship co-funded by the National Breast Cancer Foundation and Cure Cancer Australia Foundation

• 2011: Director’s Prize PhD award

1. Van Ineveld R.L., Collot R., …, Rios A.C. Multispectral confocal 3D imaging of intact healthy and tumor tissue using mLSR-3D (Nature Protocols, Dec. 2022)

2. Rios A.C. Resolving the spatial heterogeneity of cancer in 3D. (Nature Reviews Cancer, Tools of the Trade, Aug 2022)

3. Dekkers J.F., Alieva M., …, Rios A.C. Behavioral-transcriptomic landscape of engineered T cells targeting human cancer organoids (Nature Biotechnology, Jul 2022)

4. van Ineveld R.L., van Vliet E., Wehrens E.J., …, Rios A.C. 3D imaging for driving cancer discovery. Review. (EMBO J, Apr 2022)

5. van Ineveld R.L., Kleinnijenhuis M., …, Rios A.C. Revealing the spatio-phenotypic patterning of cells in healthy and tumor tissues with mLSR-3D and STAPL-3D (Nature Biotechnology, Jun 2021).

6. Dekkers J.F., …, Rios A.C. Long-term culture, genetic manipulation of human normal and breast cancer organoids. (Nature Protocols, Mar 2021).

7. Dawson C.A., …, Rios A.C. & Visvader J.E. Intravital microscopy of dynamic single-cell behaviour in mouse mammary tissue. (Nature Protocols, Mar 2021).

8. Wellens L.W., Deken M.M., …, Rios A.C. Anti-GD2-IRDye800CW as a targeted probe for fluorescence-guided surgery in neuroblastoma. (Scientific Reports, Oct 2020)

9. Dawson C.A., …, Rios A.C. & Visvader J.E. Tissue-resident ductal macrophages survey the mammary epithelium and facilitate tissue remodelling. (Nature Cell Biology, May 2020).

10. Dekkers J.F., …, Visvader J.E., Clevers H., Rios A.C. High-resolution three-dimensional imaging of fixed and cleared organoids. (Nature Protocols, Jun 2019)

11. Rios A.C., …, Visvader J.E. Intraclonal plasticity in mammary tumors revealed through Large-scale Single-cell Resolution 3D imaging. (Cancer Cell, Jun 2019

12. Rios A.C., Clevers H. Imaging organoids: a bright future ahead. Review. (Nature Methods, Jan 2018)

13. Rios A.C., Fu N.Y., Lindeman G.J. & Visvader J.E. In situ identification of bipotent stem cells in the mammary gland. (Nature, Feb 2014)

14. · Rios A.C., Marcelle C. & Serralbo O. Gene loss-of-function and live imaging in chick embryos. (Methods Molecular Biology, 2012)

15. Rios A.C., …, Marcelle C. Neural crest regulates myogenesis through the transient activation of NOTCH. (Nature, May 2011)

Rene H. Medema started his career in 1989 in the lab of Hans Bos in Leiden as a PhD student working on signal transduction by p21ras. After his PhD he moved to the laboratory of Prof. Dr. R.A. Weinberg (Whitehead Institute, Cambridge, MA) for his postdoctoral training, working on cell cycle control. As an independent group leader he continued to study cell cycle control, first at the University Medical Center Utrecht (1995-2000) and subsequently at the Netherlands Cancer Institute (2001-2005). In 2005 he moved back to Utrecht to become professor in Experimental Oncology. In 2012, he was appointed director of research at the Netherlands Cancer Institute.

His group has made several key contributions to the general understanding of control of the cell cycle by Forkhead transcription factors, FoxO and FoxM1. In addition, work from his group has provided more insight on the role of motor proteins in spindle assembly and the consequences of chromosome missegregation on the genomic stability and viability of a tumor cell. His group was the first to show that recovery from a DNA damage-induced arrest is controlled by Polo-like kinase-1 in 2004, and his lab has since provided several major contributions to our understanding of the recovery process.

• 2013: Appointed member of the European Academy of Cancer Sciences

• 2013: Appointed member of the KNAW (Royal Netherlands Academy of Arts and Sciences)

• 2012: Elected member of the Academia Europea

• 2009: EMBO membership

• 2004: VICI Laureate

1. Friskes, A., Koob, L., Krenning, L., Severson, T.M., Koeleman, E.S., Vergara, X., Schubert, M., van den Berg, J., Evers, B., Manjón, A.G., Joosten, S., Kim, Y., Zwart, W., Medema, R.H. (2022). Double-strand break toxicity is chromatin context independent. Nucl. Acid Res. 50(17), 9930.

2. Ferninga, F.M., Raaijmakers, J.A., Hadders, M.A., Vaarting, C., Macůrek, L., Heitink, L., Krenning, L., Medema, R.H. (2018). Persistent DNA repair intermediates induce senescence. Nat. Commun. 9(1), 1.

3. Krenning, L., Feringa, F. M., Shaltiel, I.A., van den Berg, J., & Medema, R.H. (2014). Transient activation of p53 in G2 phase is sufficient to induce senescence. Molecular cell, 55(1), 59-72.

4. Janssen, A., van der Burg, M., Szuhai, K., Kops, G. J., & Medema, R.H. (2011). Chromosome segregation errors as a cause of DNA damage and structural chromosome aberrations. Science, 333(6051), 1895-1898.

5. Macůrek, L., Lindqvist, A., Lim, D., Lampson, M.A., Klompmaker, R., Freire, R., ... & Medema, R.H. (2008). Polo-like kinase-1 is activated by aurora A to promote checkpoint recovery. Nature, 455(7209), 119.

Starting from the molecular analysis of DNA repair in mammals in 1981 by cloning many human DNA repair genes, which enabled elucidation of the underlying mechanisms and resolved the basis of rare human repair syndromes, we embarked upon the generation of a large series of mouse repair mutants, which we found to display accelerated but fully bona fideaging. This allowed us to reveal time- and exposure-dependent accumulation of DNA damage as the main cause of systemic aging. Whereas DNA-damage-induced mutagenesis underlies carcinogenesis, accumulated DNA damage in proliferating cells also arrests cell cycle progression inducing senescence. In non-dividing cells accumulation of DNA damage was found to interfere with transcription, to lower and skew the transcriptional output, leading to cellular functional decline and cell death and hence aging of the soma. Intriguingly, we found that aging caused by DNA-damage-induced transcription stress, simultaneously triggered a potent and interesting anti-aging, anti-cancer ‘survival’ response, which prioritizes resilience above growth. Caloric restriction (CR), which delays aging, induces a similar response. Applying calorie restriction to progeroid repair mutant mice and patients strongly delayed accelerated aging and even dramatically improved neurofunction, partially reverting neurodegeneration.

As DNA damage is the main culprit for systemic aging, this implies that most genotoxic (anti-cancer) treatments including chemo- and radiotherapy are predicted to cause features of premature aging, consistent with epidemiological studies. Since ~90% of pediatric patients are cured for a large part by virtue of chemotherapy, and ex-patients have a long life expectancy, the long-term pro-aging side effects, which significantly affect well being and QoL, constitute one of the most pressing problems in (pediatric) oncology. However, as outlined above, nutritional interventions are able to delay aging and can trigger a potent ‘survival response’, which boosts resilience and defence systems. These ingredients form the basis of several new research directions with promising perspectives in oncology, surgery and neurodegeneration, which we currently pursue in the following research lines.

1. The project aims to extend our understanding of the mechanism by which CR delays aging and exerts strong benefits in repair-deficient progeroid mice and patients, particularly improving neurofunction. The anti-aging effect of CR is still largely unknown. A very relevant observation we made is that CR reduces genome-wide transcription stress, indicating it lowers levels of DNA lesions. As DNA damage causes systemic aging, this finding reveals how CR delays aging, extends lifespan and even allows improved neurofunction. Particularly, we would like to know how CR reduces DNA damage and to get insight into the mechanism by which neurodegeneration is halted and in part even reverted, which is relevant for ex-(pediatric)cancer patients experiencing features of accelerated aging. These studies also aim to identify the components in food that are responsible for the benefits of CR and to search for effective CR-mimicking agents or treatments.

2. The ‘survival’ response triggered by CR and accelerated aging induces potent protection against a wide range of stresses. We have shown that pre-treatment fasting (1-3 days water only) in mice induces an exceptionally strong protection against ischemia reperfusion injury (IRI) that occurs after clamping blood supply to kidney and liver. To see whether and to which extent 2-3 days pre-treatment fasting also reduces IRI and improves recovery associated with (oncological) surgery and organ transplantation in humans we have initiated two randomised controlled clinical trials:

   1. The FIURTT study, Fasting Intervention for children with Unilateral Renal Tumours to reduce Toxicity, and

   2. The FAST trial, Fasting before live kidney donation, effect on donor wellbeing and postoperative recovery.

   3. In addition, we started the KetoHeppy investigation, KETOgenic diet therapy in patients with HEPatocellular adenoma. Next to these clinical studies we are performing in vitrostudies at the level of cultured cells, organoids as well as human and mouse organotypical slices to examine the effect of CR-mimicking conditions on metabolism and stress resistance.

3. To investigate whether pre-treatment fasting also induces resistance to the short- and long-term side effects of chemo- and radiotherapy we are examining the response of fasting/CR in healthy and PDX-harbouring mice on different types of anti-cancer treatment. Promising initial results have been obtained. This serves as a steppingstone to clinical trials in pediatric and possibly adult cancer patients. The in vitrosystems may also enable the development of a screening platform for CR mimetics or compounds/treatments which synergize with CR.

4. Finally, our progeroid mouse repair mutants appeared superior models for Alzheimer’s disease and other dementias and displayed an extraordinary beneficial response to CR. This was even surpassed by applying CR to the first repair-deficient TTD patient, revealing that the mouse model is highly valid for humans. Moreover, we found that CR also alleviated DNA-damage-driven transcription stress in the brain of the mice, and preliminary findings indicate that CR diminished amyloid-like as well as other pathogenic protein aggregates, which spontaneously develop in our repair mutants. These observations may address a tremendous unmet medical need and provide the basis for research directed at better understanding the molecular mechanisms involved and translation to patients, including (ex-)pediatric patients suffering from cognitive decline.

In summary, our research aims to elucidate the surprisingly simple, globally-applicable, inexpensive potential of nutritional interventions on (accelerated) aging and on health and to pioneer their application in important areas in medicine, including surgery, organ transplantation, chemo- and radiotherapy and proteinopathies in common forms of dementia.

• 2021: Official recognition of the Erasmus MC clinical expertise center for Rare Genome Instability Disorders, a multi-disciplinary clinic for children with DNA repair syndromes, initiated by Jan Hoeijmakers

• 2020: Ammodo Research Team Award” to ‘Guardians and Caretakers of the Genome’ together with other members of the Erasmus Dept. Mol. Genet.

• 2019: “EMGS Award” of the Environmental Mutagenesis and Genetics Soc. (Washington DC)

• 2018: Knowledge Ambassador of the City of Rotterdam

• 2017: International Olav Thon Foundation personal Award

• 2017: Honorary TEFAF Oncology Chair of the Maastricht Univ. Medical Center

• 2016: NVHG Galjaard Prize of the Netherlands Society of Human Genetics

• 2016: Professor International Faculty, Cologne University (Cologne, Guest Professor)

• 2016: Selected for the Nobel-Forum lecture at the Karolinska Institute

• 2015: ERC PoC grant DEMENTIA European Research Council

• 2014: Consulted by the Nobel Committee for the Nobel Prize in Chemistry for DNA repair (2014-2015)

• 2013: Royal distinction Knight in the Order of the Dutch Lion for important scientific achievements in the area of cancer and aging research (2013).

• 2012: Mendel Medal on the occasion of the 190th anniversary of Mendel’s birth

• 2011: Koningin Wilhelmina Research Prize of the Dutch Cancer Society, for research on DNA damage response in prostate and urinary bladder cancer (2M€) (Leiden, 2011)

• 2011: Academy Professor of the Royal Academy of Sciences of The Netherlands (KNAW), First Academy Professor new style in the broad domain of Beta sciences

• 2011: Cancer Research Prize of the Charles Rudolph Brupbacher Stiftung for research on the role of genome stability in cancer and aging, shared with Bert Vogelstein

• 2008: ERC Advanced Grant DamAge – Multi-disciplinary Sciences European Research Council

• 2008: Seneca Medaille des Industrie-Clubs für Altensforschung Prize, for pioneering research on the molecular basis of aging (First awardee)

• 2001: ‘Josephine Nefkens Prize’ for cancer research

• 2000: Elected member of KNAW (section ‘Medicine’, dept. ‘Physics’)

• 2000: ‘EC-Descartes’ Award for European collaboration on DNA repair

• 2000: ‘Van Gogh’ Prize from the Dutch Science Organization

• 2000: ‘Descartes-Huygens’ Award for French-Dutch scientific collaborations

• 1999: ‘Spinoza’ Prize, most recognized prize of the Dutch Science Organization

• 1995: The very prestigious 'Louis Jeantet' Prize for Medical Research in Europe for the entire work on DNA repair (Geneva, 1995)

• 1995: EMBO

• 1986: 'Snoo van t' Hoogerhuys' Prize (isolation of the first human DNA repair gene)

• 1983: 'Harold Quintus Bosz' Prize (for the discovery of the molecular mechanism of antigenic variation in trypanosomes, PhD thesis)

1. Hoeijmakers, J. H. (2001). Genome maintenance mechanisms for preventing cancer. nature, 411(6835), 366.

2. De Boer, J., Andressoo, J. O., de Wit, J., Huijmans, J., Beems, R. B., van Steeg, H., ... & Hoeijmakers, J.H. (2002). Premature aging in mice deficient in DNA repair and transcription. Science, 296(5571), 1276-1279.

3. Niedernhofer, L. J., Garinis, G. A., Raams, A., Lalai, A. S., Robinson, A. R., Appeldoorn, E., ... & Hoeijmakers, J.H. (2006). A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis. Nature, 444(7122), 1038.

4. Marteijn, J. A., Lans, H., Vermeulen, W., & Hoeijmakers, J. H. (2014). Understanding nucleotide excision repair and its roles in cancer and ageing. Nature reviews Molecular cell biology, 15(7), 465.

5. Vermeij, W. P., Dollé, M. T., Reiling, E., Jaarsma, D., Payan-Gomez, C., Bombardieri, C. R., ... & Hoeijmakers, J.H. (2016). Restricted diet delays accelerated ageing and genomic stress in DNA-repair-deficient mice. Nature, 537(7620), 427.

6. Schumacher, B., Pothof, J., Vijg, J., & Hoeijmakers, J.H. (2021). The central role of DNA damage in the ageing process. Nature, 592(7856), 695.

Jarno Drost obtained his Master’s degree in Biomedical Sciences cum laude in 2005 from the Free University in Amsterdam. He received his PhD from the Erasmus University Rotterdam for his work on the identification of new tumor suppressor genes in the P53 pathway in the research group of Reuven Agami at the Netherlands Cancer Institute in Amsterdam.

Subsequently, Jarno joined the group of Hans Clevers at the Hubrecht Institute for his postdoctoral training where he exploited the organoid technology for cancer research. He developed colorectal cancer (CRC) progression models by introducing combinations of the most commonly mutated CRC genes in human small intestinal and colonic organoids using CRISPR/Cas9 genome editing. He used these models to study multistep tumorigenesis. For his work he received an NWO/Veni fellowship and the Dr. Patrick Hanlo Award for best postdoctoral researcher of the Hubrecht Institute.

In November 2016, he became a group leader at the Princess Máxima Center for pediatric oncology. His group studies the molecular alterations underlying pediatric solid tumors and uses novel pre-clinical model systems to identify therapeutic targets. He was granted a Bas Mulder young investigator award from the Dutch Cancer Society (KWF), the ERC Starting and NWO-Vidi grants, and the AACR St. Baldrick’s career development award for emerging leaders in the field of pediatric oncology.

• 2021: NWO-Vidi grant

• 2021: Achieved tenure at Princess Máxima Center for Pediatric Oncology

• 2020: AACR St. Baldrick’s career development award

• 2019: European Research Council (ERC) Starting Grant

• 2017: Dr. Patrick Hanlo Award for best postdoctoral researcher of the Hubrecht Institute

• 2016: Bas Mulder young investigator award from the Dutch Cancer Society (KWF)

• 2014: NWO (Netherlands organization for scientific research) VENI award

1. Meister, M.T., Groot Koerkamp, M.J.A., de Souza, T., Breunis, W.B., Frazer-Mendelewska, E., Brok, M., DeMartino, J., Manders, F., Calandrini, C., Kerstens, H.H.D., Janse, A., Dolman, M.E.M., Eising, S., Langenberg, K.P.S., van Tuil, M., Knops, R.R.G., van Scheltinga, S.T., Hiemcke-Jiwa, L.S., Flucke, U., Merks, J.H.M., van Noesel, M.M., Tops, B.B.J., Hehir-Kwa, J.Y., Kemmeren, P., Molenaar, J.J., van de Wetering, M., van Boxtel, R., Drost, J.#, Holstege, F.C.P#. Mesenchymal tumor organoid models recapitulate rhabdomyosarcoma subtypes. EMBO Molecular Medicine 2022 Aug 2; e16001. doi: 10.15252/emmm.202216001.

2. Calandrini, C., van Hooff, S.R., Paassen, I., Ayyildiz, D., Derakhshan, S., Dolman, M.E.M., Langenberg, K.P.S., van de Ven, M., de Heus, C., Liv, N., Kool, M., de Krijger, R.R., Tytgat, G.A.M., van den Heuvel-Eibrink, M.M., Molenaar, J.J., Drost, J. Organoid-based drug screening reveals neddylation as therapeutic target for malignant rhabdoid tumors. Cell Reports 2021 Aug 24; 36(8):109568. doi: 10.1016/j.celrep.2021.109568.

3. Young, M.D.*, Mitchell, T.J.*, Custers, L.*, Margaritis, T., Morales-Rodriguez, F., Kwakwa, K., Khabirova, E., Kildisiute, G., Oliver, T.R.W., de Krijger, R.R., van den Heuvel-Eibrink, M.M., Comitani, F., Piapi, A., Bugallo-Blanco, E., Thevanesan, C., Burke, C., Prigmore, E., Ambridge, K., Roberts, K., Vieira Braga, F.A., Coorens, T.H.H., Del Valle, I., Wilbrey-Clark, A., Mamanova, L., Stewart, G.D., Gnanapragasam, V.J., Rampling, D., Sebire, N., Coleman, N., Hook, L., Warren, A., Haniffa, M., Kool, M., Pfister, S.M., Achermann, J.C., He, X., Barker, R.A., Shlien, A., Bayraktar, O.A, Teichmann, S., Holstege, F.C., Meyer, K.B., Drost, J.#, Straathof, K.#, Behjati, S.#. Single cell derived mRNA signals across human kidney tumors. Nature Communications 2021 Jun 23; 12(1):3896. doi: 10.1038/s41467-021-23949-5.

4. Custers, L.*, Khabirova, E.*, Coorens, T.H.H.*, Oliver, T.R.W., Calandrini, C., Young, M.D., Vieira Braga, F.A., Ellis, P., Mamanova, L., Segers, H., Maat, A., Kool, M., Hoving, E.W., van den Heuvel-Eibrink, M.M., Nicholson, J., Straathof, K., Hook, L., de Krijger, R.R., Trayers, C., Allinson, K., Behjati, S.#, Drost, J.#. Somatic mutations and single-cell transcriptomes reveal the root of malignant rhabdoid tumours. Nature Communications 2021 Mar 3; 12(1):1407. doi: 10.1038/s41467-021-21675-6.

5. Calandrini, C.*, Schutgens, F.*, Oka, R., Margaritis, T., Candelli, T., Mathijsen, L., Ammerlaan, C., van Ineveld, R.L., Derakhshan, S., de Haan, S., Dolman, E., Lijnzaad, P., Custers, L., Begthel, H., Kerstens, H.H.D., Rookmaker, M., Verhaar, M., Tytgat, G.A.M., Kemmeren, P., de Krijger, R.R., Al-Saadi, R., Pritchard-Jones, K., Kool, M., Rios, A., van den Heuvel-Eibrink, M.M., Molenaar, J., van Boxtel, R., Holstege, F.C.P., Clevers, H., Drost, J. An organoid biobank for childhood kidney cancers that captures disease and tissue heterogeneity. Nature Communications 2020;11(1):1310. doi: 10.1038/s41467-020-15155-6.

The research group of Ruben van Boxtel has pioneered the development of experimental and computational approaches to study the genomes of human stem cells. Using these methods, his group showed that mutation accumulation varies across different tissues throughout human life. In 2017, Ruben was appointed as a group leader at the Princess Máxima Center for Pediatric Oncology, where he focusses on studying why children get leukemia and lymphoma, and what the genotoxic effects of treatment are in the hematopoietic system. Using in-depth mutational analyses, the group of Ruben has discovered mutational cancer signatures caused by a genotoxic gut bacterium and an antiviral drug.

Ruben received an NWO Vidi award in 2017 by the Netherlands Organization for Scientific Research, which is a prestigious personal Dutch grant for starting group leaders, for his research on studying genomic integrity of human stem cells throughout life. In addition, Ruben received an ERC Consolidator award by the European Research Council in 2019, which is the most prestigious grant for established young research leaders in Europe, to study the causes of therapy-related myeloid neoplasms in childhood cancer survivors. In the same year, he was selected as an Oncode Investigator, which a collective institute bringing together the best fundamental cancer researchers in the Netherlands. In 2022, Ruben received the NYSCF Robertson Stem Cell Investigator Award for his work on studying long-term toxicity in the hematopoietic system of childhood cancer survivors.

• 2022: New York Stem Cell Foundation Robertson Stem Cell Investigator Award

• 2022: Ammodo Science Award for ground-breaking research (team award with Omnes Pro Uno)

• 2019: ERC Consolidator grant

• 2019: Selected Oncode member

• 2017: NWO VIDI Award

1. Bertrums EJM, Rosendahl Huber AKM, de Kanter JK, Brandsma AM, van Leeuwen AJCN, Verheul M, van den Heuvel-Eibrink MM, Oka R, van Roosmalen MJ, de Groot-Kruseman HA, Zwaan CM, Goemans BF, van Boxtel R. Elevated mutational age in blood of children treated for cancer contributes to therapy-related myeloid neoplasms. Cancer Discovery (2022) 12:1860-1872.

2. de Kanter JK, Peci F, Bertrums E, Rosendahl Huber A, van Leeuwen A, van Roosmalen MJ, Manders F, Verheul M, Oka R, Brandsma AM, Bierings M, Belderbos M, van Boxtel R. Antiviral treatment causes a unique mutational signature in cancers of transplantation recipients. Cell Stem Cell (2021) 28:1726-1739.e6.

3. Brandsma AM, Bertrums EJM, van Roosmalen MJ, Hofman DA, Oka R, Verheul M, Manders F, Ubels J, Belderbos ME, van Boxtel R. Mutation signatures of pediatric acute myeloid leukemia and normal blood progenitors associated with differential patient outcomes. Blood Cancer Discovery (2021) 2:484-499.

4. Pleguezuelos-Manzano C, Puschhof J, Rosendahl Huber A, van Hoeck A, Wood HM, Nomburg J, Gurjao C, Manders F, Dalmasso G, Stege PB, Paganelli FL, Geurts MH, Beumer J, Mizutani T, van der Linden R, van Elst S; Genomics England Research Consortium, Top J, Willems RJL, Giannakis M, Bonnet R, Quirke P, Meyerson M, Cuppen E, van Boxtel R*,Clevers H*. Mutational signature in colorectal cancer caused by genotoxic pks+ E. coli. Nature (2020) 580:269-273. *co-corresponding authors

5. Osorio FG, Rosendahl Huber A, Oka R, Verheul M, Patel SH, Karlijn Hasaart K, de la Fonteijne L, Varela I, Camargo FD, van Boxtel R. Somatic Mutations Reveal Lineage Relationships
   and Age-Related Mutagenesis in Human Hematopoiesis. Cell Reports (2018) 25: 2308-2316

6. 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. Nature (2016) 538:260-264.