PI: Prof.dr. Hans Clevers
Current treatment for pediatric solid cancer consists of chemotherapy, surgery, radiotherapy and in some cases immunotherapy. Few treatment options however exist for refractory or recurrent disease, with almost invariably a fatal outcome as a consequence. Very little innovation has been achieved in the past decade. We consider this a consequence of the lack of relevant experimental in vitro and in vivo models for functional studies of tumor biology.
There is a dire need for novel in vitro culture-based systems to study solid pediatric cancers. Such systems should preserve the naturally existing cellular hierarchy within the tumor cell population. Tumor-derive organoids fill this gap. Organoids hold promise to revolutionize personalized tumor treatment.
Recent developments in our laboratory have resulted in development of long-term culture conditions for healthy organ- and tumor-derived cells. This so called organoid technology allows to grow large quantities of tumor material from a small biopsy or from resected material. The technology has by now been optimized for various cancer indications including colon, pancreas, prostate breast, lung, and ovarian cancers. The organoid culture media for different tumor indications differ in growth factor composition. For most solid pediatric cancers, however, such technology is not yet available. Upon optimizing growth factor cocktails, we expect to be able to grow pediatric cancer organoids as well. This will subsequently allow us to generate living cancer organoid biobanks that will help to study the biology of pediatric tumors and test new drug treatments.
Neuroblastoma is a malignant expansion of neuroblasts. These neuroblasts originate from neural crest cells that migrate through the developing body and eventually differentiate into specialized cell types and body structures like melanocytes, facial bones, the parasympathetic nervous system and the medulla of the adrenal gland. About half of all neuroblastomas arise in the adrenal gland, when neuroblasts are arrested in their active cycling state. To study the signals that drive proliferation of healthy and malignant neuroblasts, we use single cell analysis to make an inventory of the receptors and ligands expressed by the cells in the developing adrenal gland. These signals may include potential drug targets for novel neuroblastoma therapy.
Ewing family sarcomas are bone associated tumors that are caused by a genomic translocation involving Ewing Sarcoma Region 1. In desmoplastic small round cell tumors (DSRCT), the translocation fuses EWSR1 and WT1, but the mechanism by which the resulting chimeric EWS-WT1 protein transforms healthy cells is unknown. We have successfully derived organoids from DSRCT patients and are using these cancer organoids to study the mechanism of transformation in detail.
Huch, M., Gehart, H., van Boxtel, R., Hamer, K., Blokzijl, F., Verstegen, M., Ellis, E., van Wenum, M., Fuchs, S., de Ligt, J., van de Wetering, M., Sasaki, N., Boers, S., Kemperman, H., de Jonge, J. IJzermans, J., Niewenhuis, E., Hoekstra, R., Strom, S., Vries, R., van der Laan, L., 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
Boj, S.F., Hwang, C.I., Baker, L.A., Chio, I.I., Engle, D.D., Corbo, V., Jager, M., Ponz-Sarvise, M., Tiriac, H., Spector, M.S., Gracanin, A., Oni, T., Yu, K.H., van Boxtel, R., Huch, M., Rivera, K.D., Wilson, J.P., Feigin, M.E., Öhlund, D., Handly-Santana, A., Ardito-Abraham, C.M., Ludwig, M., Elyada, E., Alagesan, B., Biffi, G., Yordanov, G.N., Delcuze, B., Creighton, B., Wright, K., Park, Y., Morsink, F.H., Molenaar, I.Q., Borel Rinkes, I.H., Cuppen, E., Hao, Y., Jin, Y., Nijman, I.J., Iacobuzio-Donahue, C., Leach, S.D., Pappin, D.J., Hammell, M., Klimstra, D.S., Basturk, O., Hruban RH, Offerhaus GJ, Vries RG, Clevers H, Tuveson DA. Organoid models of human and mouse ductal pancreatic cancer. (2015) Cell 160: 324-33 PubMed PMID: 25557080
van de Wetering, M., Francies, H.E., Francis, J.M., Bounova, G., Iorio, F., Pronk, A., van Houdt, W., van Gorp, J., Taylor-Weiner, A., Kester, L., McLaren-Douglas, A., Blokker, J., Jaksani, S., Bartfeld, S., Volckman, R., van Sluis, P., Li, V.S.W., Seepo, S., Sekhar Pedamallu, C., Cibulskis, C., Carter, S.L., McKenna, A., Lawrence, M.S., Lichtenstein, L., Stewart, C., Koster, J., Versteeg, R., van Oudenaarden, A., Saez-Rodriguez, J., Vries, R.G.J., Getz, G., Wessels, L., Stratton, M.R., McDermott, U., Meyerson, M., Garnett, M.J., Clevers, H. Prospective derivation of a 'Living Organoid Biobank' of colorectal cancer patients. (2015) Cell 161: 933-945 PubMed PMID: 25957691
Sachs N, de Ligt J, Kopper O, Gogola E, Bounova G, Weeber F, Balgobind AV, Wind K, Gracanin A, Begthel H, Korving J, van Boxtel R, Duarte AA, Lelieveld D, van Hoeck A, Ernst RF, Blokzijl F, Nijman IJ, Hoogstraat M, van de Ven M, Egan DA, Zinzalla V, Moll J, Boj SF, Voest EE, Wessels L, van Diest PJ, Rottenberg S, Vries RGJ, Cuppen E, Clevers H. A Living Biobank of Breast Cancer Organoids Captures Disease Heterogeneity. (2018) Cell 172, 373–386 PubMed PMID: 29224780
Roerink, S.F., Sasaki, N., Lee-Six, H., Young, M., Alexandrov, L.B., Behjati, S., Mitchell, T.J., Grossmann, S., Lightfoot, H., Egan, D.A., Pronk, A., Smakman, N., van Gorp, J., Anderson, E., Gamble, S.J., Alder, C., van de Wetering, M., Campbell, P.J., Stratton, MR, and Clevers H. Intra-tumour diversification incolorectal cancer at the single-cell level. (2018) Nature 556, 457-462 PubMed PMID: 29643510