Snippert group
Plasticity and genomic instability
Cancer is a highly heterogeneous disease, with individual cells exhibiting diverse morphological, molecular, and functional characteristics. This variability poses a major challenge for developing therapies that effectively target all cancer cells, in both adult and pediatric patients. The Snippert group main interest is to use patient-derived (cancer) organoids, advanced molecular genetics, and state-of-the-art imaging to study how cellular plasticity and genomic instability drive tumor evolution and influence responses to therapy.
Contact
Hugo Snippert
Advancing organoid technology
At its core, our lab is motivated to develop and pioneer cutting-edge genetic tools to advance patient organoid models. Generally, we like to adapt, modify and improve existing molecular genetics that is commonly applied in mouse models, to generate patient organoids with sophisticated genetic knock-ins, conditional knock-outs and targeted transgenes. These tools allow us to mark, track and manipulate (tumor) cells with unprecedented control, enabling a deeper understanding of cellular function.
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With fluorescent knock-ins in cell type marker genes, we study cell biology of specific cell types, plasticity of cell states and their dynamic behavior in real-time -under normal conditions, during regeneration, in cancer and upon exposure to external stimuli or therapies. For example, we use real-time imaging, sometimes paired with single-cell genome seq., to examine the level of chromosomal instability in cancer and to track the tempo, pattern and propagation potential of genomic alterations within cell populations.
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Alternatively, we use and develop fluorescent biosensors to study signaling pathway activity in real-time and with single-cell resolution, and harness organoid technology to pioneer unexplored cell biology that underlies functioning of primary human cells.
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“Our ambition is to understand the cause and consequence of cellular heterogeneity during tumor evolution and therapy response”
Dr. Hugo Snippert
Research group leader
Pre-cancer to cancer prevention
We employ colon cancer as our prototype cancer model to study tumor progression, with well-characterized signaling pathways affected by driver mutations. These drivers are typically acquired early during tumor progression, while genetic drivers of metastasis formation have not been identified. A dominant role is attributed for the tumor microenvironment in the acquisition of malignant growth behavior, which includes the induction of cellular plasticity.
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An evolutionary bottleneck in the progression of tumors, is the so-called malignant transformation that demarcates the transitioning from pre-malignancy to cancer. The Snippert lab is particularly interested in the evolution of cellular behavior and phenotypes during the transitory stages from pre-cancer to cancer. Experimentally, these early stages remain largely unexplored territory as there is strong study bias towards late-stage cancers. The Snippert lab uses an integrated approach of descriptive (spatial) single-cell atlases of early cancers, with experimental explorations using functional organoid models.
Grants and awards
Key publications
- Key publications
Buissant des Amorie JR, Betjes MA, Bernink JH, Hageman JH, Geurts VE, Begthel H, Laskaris D, Heinz MC, Jordens I, Vinck T, Houtekamer RM, Verlaan-Klink I, Brunner SR, van Rheenen J, Gloerich M, Clevers H, Tans SJ, van Zon JS, Snippert HJG. Intestinal tuft cell subtypes represent successive stages of maturation driven by crypt-villus signaling gradients. Nat Commun. 2025
Kayhanian H*, Cross W*, van der Horst SEM*, Barmpoutis P*, Lakatos E*, Caravagna G, Zapata L, Van Hoeck A, Middelkamp S, Litchfield K, Steele C, Waddingham W, Patel D, Milite S, Jin C, Baker AM, Alexander DC, Khan K, Hochhauser D, Novelli M, Werner B, van Boxtel R, Hageman JH, Buissant des Amorie JR, Linares J, Ligtenberg MJL, Nagtegaal ID, Laclé MM, Moons LMG, Brosens LAA, Pillay N, Sottoriva A, Graham TA, Rodriguez-Justo M, Shiu KK, Snippert HJG#, Jansen M#. Homopolymer switches mediate adaptive mutability in mismatch repair-deficient colorectal cancer. Nat Genet. 2024
Boon NJ, Oliveira RA, Körner PR, Kochavi A, Mertens S, Malka Y, Voogd R, van der Horst SEM, Huismans MA, Smabers LP, Draper JM, Wessels LFA, Haahr P, Roodhart JML, Schumacher TNM, Snippert HJ, Agami R, Brummelkamp TR. DNA damage induces p53-independent apoptosis through ribosome stalling. Science. 2024
Mertens S, Huismans MA, Verissimo CS, Ponsioen B, Overmeer R, Proost N, van Tellingen O, van de Ven M, Begthel H, Boj SF, Clevers H, Roodhart JML, Bos JL, Snippert HJG. Drug-repurposing screen on patient-derived organoids identifies therapy-induced vulnerability in KRAS-mutant colon cancer. Cell Rep. 2023
Heinz MC*, Peters NA*, Oost KC, Lindeboom RGH, van Voorthuijsen L, Fumagalli A, van der Net MC, de Medeiros G, Hageman JH, Verlaan-Klink I, Borel Rinkes IHM, Liberali P, Gloerich M, van Rheenen J, Vermeulen M, Kranenburg O#, Snippert HJG#. Liver Colonization by Colorectal Cancer Metastases Requires YAP-Controlled Plasticity at the Micrometastatic Stage. Cancer Res. 2022
Bollen Y, Stelloo E, van Leenen P, van den Bos M, Ponsioen B, Lu B, van Roosmalen MJ, Bolhaqueiro ACF, Kimberley C, Mossner M, Cross WCH, Besselink NJM, van der Roest B, Boymans S, Oost KC, de Vries SG, Rehmann H, Cuppen E, Lens SMA, Kops GJPL, Kloosterman WP, Terstappen LWMM, Barnes CP, Sottoriva A, Graham TA, Snippert HJG. Reconstructing single-cell karyotype alterations in colorectal cancer identifies punctuated and gradual diversification patterns. Nat Genet. 2021
Ponsioen B, Post JB, Buissant des Amorie JR, Laskaris D, van Ineveld RL, Kersten S, Bertotti A, Sassi F, Sipieter F, Cappe B, Mertens S, Verlaan-Klink I, Boj SF, Vries RGJ, Rehmann H, Vandenabeele P, Riquet FB, Trusolino L, Bos JL, Snippert HJG. Quantifying single-cell ERK dynamics in colorectal cancer organoids reveals EGFR as an amplifier of oncogenic MAPK pathway signalling. Nat Cell Biol. 2021
Fumagalli A, Oost KC, Kester L, Morgner J, Bornes L, Bruens L, Spaargaren L, Azkanaz M, Schelfhorst T, Beerling E, Heinz MC, Postrach D, Seinstra D, Sieuwerts AM, Martens JWM, van der Elst S, van Baalen M, Bhowmick D, Vrisekoop N, Ellenbroek SIJ, Suijkerbuijk SJE, Snippert HJ, van Rheenen J. Plasticity of Lgr5-Negative Cancer Cells Drives Metastasis in Colorectal Cancer. Cell Stem Cell. 2020
Bolhaqueiro ACF*, Ponsioen B*, Bakker B, Klaasen SJ, Kucukkose E, van Jaarsveld RH, Vivié J, Verlaan-Klink I, Hami N, Spierings DCJ, Sasaki N, Dutta D, Boj SF, Vries RGJ, Lansdorp PM, van de Wetering M, van Oudenaarden A, Clevers H, Kranenburg O, Foijer F, Snippert HJG#, Kops GJPL#. Ongoing chromosomal instability and karyotype evolution in human colorectal cancer organoids. Nat Genet. 2019
Kopper O, de Witte CJ, Lõhmussaar K, Valle-Inclan JE, Hami N, Kester L, Balgobind AV, Korving J, Proost N, Begthel H, van Wijk LM, Revilla SA, Theeuwsen R, van de Ven M, van Roosmalen MJ, Ponsioen B, Ho VWH, Neel BG, Bosse T, Gaarenstroom KN, Vrieling H, Vreeswijk MPG, van Diest PJ, Witteveen PO, Jonges T, Bos JL, van Oudenaarden A, Zweemer RP, Snippert HJG, Kloosterman WP, Clevers H. An organoid platform for ovarian cancer captures intra- and interpatient heterogeneity. Nat Med. 2019
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